San Antonio Breast Cancer Symposium 2009
Some say there is TOO MUCH “Awareness” and we get enough Research... NOT SO:
[1080] The Relationship between Breast Cancer and Research; a Bibliometric Study. Glynn RW, Chin JZ, Kerin MJ, Sweeney KJ National University of Ireland, Galway, Galway, Ireland Background: Thousands of articles are published every year in the medical literature relating to the diagnosis and treatment of cancer patients. An area of contention of late has been the amount of research time and money being devoted to breast cancer, to what some believe is to the detriment of research into other forms of malignancy. The aims of this study were to further investigate the relationship between malignancy and research, in order to better quantify the degree to which breast cancer is being over- or under-represented in the research world. Methods: Bibliometrics is the science of studying written communication by systematic measurement and analysis of research publications. In this study, we examined research output over a one-year period for the 26 most commonly diagnosed cancers in the UK. Our strategy was based on that employed by a group in Edinburgh in 2001, and involved correlating research output with incidence and mortality statistics. In addition, we sought to elucidate changes in research output over time and then to correlate these changes with improvements in survival. The survival data used was that published by Coleman et al in 2004, and represents changes in survival over 5 year periods between 1986 and 1999 in England and Wales. Results: A total of 73,798 publications were included in this study. Breast cancer received more research attention than any other malignancy in the time period of this study. Proportional to its incidence and associated mortality, however, breast cancer was markedly underrepresented. This relationship was consistent across publication and study types, and in the higher impact journals. There was a strong positive correlation between improvement in 5-year survival and research output (p = 0.003). Those malignancies enjoying the greatest increases in output included those involving the prostate, non-hodgkins lymphoma, breast and vaginal cancer. Conclusions: This study was intended to provide a snapshot-in-time of research output in malignancy. It has shown that, on the basis of both incidence and mortality, breast cancer is not receiving disproportionate attention by the research community, contrary to popular opinion. Whilst the absolute figures clearly reflect the success of the breast cancer advocacy community in raising and maintaining the profile of the disease, the evidence suggests that, if anything, breast cancer is not receiving the interest it deserves, based on its burden to society.
HOT FLASH SEVERITY TIED TO WEIGHT GAIN
[1059] Weight Gain Is Associated with Increased Risk of Hot Flashes in Breast Cancer Survivors on Aromatase Inhibitors. Su HI, Sammel MD, Springer EL, Freeman EW, DeMichele AM, Mao JJ University of Pennsylvania, Philadelphia, PA Objective: Hot flashes in breast cancer survivors (BCS) receiving adjuvant aromatase inhibitor (AI) therapy are common, but risk factors for these symptoms are not well-defined. This study tested if body size is associated with hot flashes in BCS on AI therapy. Materials and methods: We performed a cross-sectional analysis of a cohort of postmenopausal women with Stages 0-III breast cancer receiving adjuvant AI therapy at a university hospital-based outpatient breast oncology clinic. Subjects provided patient-reported outcomes on hot flashes, current and pre-breast cancer weight and height, and additional demographic and treatment data. The primary outcome was occurrence of hot flashes. Secondary outcomes included hot flash severity and frequency. The exposures of interest were 1) current weight and 2) weight change since breast cancer diagnosis, categorized as weight loss (lost 10 pounds or more), maintenance (+/- 10 pounds), or gain (gained 10 pounds or more). Multivariable logistic regression models examined the independent association between hot flash outcomes and current weight or weight change while controlling for confounders. Results: 300 participants were enrolled at a mean age of 61 years (range 33-86) after mean duration of AI exposure of 23 months (range 1 month-9 years). 177 (59%) reported hot flashes overall, 96 (32%) reported moderate to very severe hot flashes, and 60 (20%) had at least 4 hot flashes daily. 182 (61%) experienced weight maintenance, while 81 (27%) had weight gain and 34 (11%) had weight loss. In a multivariable model, weight gain was independently associated with hot flash occurrence (OR 2.1, 95% CI 1.1-4.4) and hot flash severity (OR 2.4, 95% CI 1.4-4.9), but not hot flash frequency, after adjusting for current weight and height, age, smoking, race, prior chemotherapy and prior tamoxifen therapy. Hot flash occurrence was also significantly associated with current smoking (OR 5.1, 95% CI 1.1-24.0) and age (OR for each additional year of age 0.93, 95% CI 0.90-0.97). Current weight, alcohol use, AI type, and AI duration were not associated with any of the three outcomes. Conclusions: In an outpatient BCS population on AI therapy, weight gain is a risk factor for both hot flash occurrence and severity. Women who gained at least ten pounds since breast cancer diagnosis were two times more likely to have hot flashes than women who maintained or lost weight. These results support the thermoregulatory model of hot flashes and argue against a protective effect of body fat in this population. Support: ACS MRSG-08-110-01-CCE, ACS CCDA#-08-107-01, Pennsylvania Department of Aging
WHY EVERYONE SHOULD GET “INTIMACY AFTER BREAST CANCER” When it is released in the first week of February.....
Proof of Sexual Dysfunction from Breast Cancer Treatment
[1056] Burden of Sexual Dysfunction in Women with Breast Cancer. Goldfarb SB, Dickler MN, Fruscione M, Sit L, Jia R, Kaplan J, Barz T, Atkinson T, Hudis CA, Basch EM Memorial Sloan-Kettering Cancer Center, New York, NY Background: Sexual dysfunction is reported after chemotherapy and endocrine therapies, and causes a substantial burden on women with breast cancer. However, the prevalence and severity of sexual dysfunction in women undergoing therapy for both local and metastatic disease is not well defined. Improved understanding of sexual dysfunction may facilitate enhanced treatment and interventions in patients with breast cancer undergoing active treatment, and in survivors of this disease. Methods: We developed a survey that includes a previously validated questionnaire, the female sexual function index (FSFI), as well as an established measure of health-related quality of life (the EuroQol EQ-5D), and disease-specific items to characterize sexual dysfunction and its causes based on literature review and expert consultations. Anonymous administration of the surveys was conducted in outpatient clinic waiting areas of the Breast Cancer Center at Memorial Sloan-Kettering Cancer Center (MSKCC) and two community centers, under an IRB waiver of consent. Results: During November 2008 through May 2009, 509 women undergoing treatment for breast cancer of all stages were each queried once. The mean age was 51 (range 26-91). 87% reported current or past hormonal treatment, and 82% reported current or past chemotherapy (76% adjuvant; 24% for metastatic disease). Sexual dysfunction attributed to breast cancer or its treatment, defined as an FSFI score <26, was reported by 76% of respondents. Among these women, 316/386 (82%) patients considered their sexual symptoms to be bothersome, with 247/386 (64%) noting moderate or severe levels of bother (score >=5/10). Patients attributed their sexual dysfunction to chemotherapy in 318/373 (85%) of cases; to hormonal therapy in 221/298 (74%) of cases; and to surgery in 331/442 (66%) of cases. Other reported contributors to sexual dysfunction include a new diagnosis of breast cancer by 81% of respondents, anxiety by 82% of respondents, and change in relationship with a partner by 55% of respondents. Conclusion: Sexual dysfunction is prevalent in women treated for breast cancer and should be discussed with patients as a potential adverse effect of therapy. Assessment of sexual symptoms throughout treatment and beyond may facilitate the use of potential interventions such as lubricants, dilators, treatment modification, topical estrogens, and counseling. Future work includes a longitudinal prospective trial to further characterize the etiologies of these symptoms and a randomized controlled trial to evaluate interventions for sexual dysfunction.
What MRIs can find
[4018] Retrospective Study Assessing the Role of MRI in the Diagnostic Procedures for Early Breast Carcinoma: A Correlation of New Foci in the MRI with Tumor Pathological Features. Calvo Plaza I, Ugidos de la Verga L, Miró C, Suarez A, Perez P, Quevedo P, Parras M, Torres M, Herrero M, Buelga P, García L, Alonso P, de la Cruz JJ, López Ríos F, Hidalgo M, G Estévez L Centro Integral Oncológico Clara Campal, Madrid, Madrid, Spain; Autonoma University, Madrid, Madrid, Spain Purpose: To analyze the role of MRI in the detection of additional disease and the need to perform additional biopsies in early breast carcinoma patients. In addition, to correlate the detection of new foci with tumor pathological features. Methods: Early breast carcinoma patients that had undergone a MRI as well as a mammography as diagnostic procedures were included in the study. The following pathologic features were studied: carcinoma type, histological grade, estrogen (ER)/progesterone (PR) receptors, HER2 and Ki67. HER2 status was established by FISH, while ER, PR and Ki67 status were established by inmunohistochemistry. Univariate analysis was conducted to ascertain significant correlation among detection of new foci and each of the tumor pathological features. Results: To date, data from 98 patients have been analyzed: median age 49 years (range: 35-79); carcinoma type: a) infiltrative ductal carcinoma (n=73, 74%), b) infiltrative lobular cancer (n=13, 13%), c)ductal carcinoma in situ (n= 6, 6%); amplified HER2 (n=18, 18%); grade III (n=33, 33%);Ki67 ≥ 25%(n=33, 33%); positive ER and PR (n=78, 79%); triple negative tumors (n=8, 8%). MRI detected additional disease in 38 cases (39%) that led to an additional biopsy in 20 cases (20%). Thirty-nine patients (39%) underwent mastectomy. A statistically significant correlation was established between the finding of new foci in MRI and high proliferative tumors through the biomarker Ki67 (cutoff ≥ 25%) (p<0.005). No other statistically significant correlation was established with any of the other pathological features analyzed. Conclusion: In patients diagnosed with early breast cancer, MRI detected the presence of additional disease in 39% of the cases, requiring an additional biopsy in 20% of the cases. Tumors with high proliferative index were significantly correlated with the detection of new foci in MRI. An update of the results will be presented at the symposium.
TNBC has better outcome if guidelines are followed
[2101] Influence of Treatment Conforming to Guidelines on Recurrence Free Survival (RFS) and Overall Survival (OS) in Triple Negative Breast Cancer. Atassi Z, Wischnewsky M, Wöckel A, Kurzeder C, Wolters R, Novopashenny I, Kreienberg R University of Ulm, Ulm, Germany; University of Bremen, Bremen, Germany Introduction: The triple negative(TN) breast cancer subtype (ER neg, PR neg, HER 2 neg) represents about 10 to 15% 0f all breast cancer types. It characterizes an aggressive phenotype with significantly worsened RFS, OS as well as specific clinical and pathological properties. The aim of this study was: 1.To assess the efficacy of guideline conforming conventional chemotherapy, local recurrence rate, distant recurrence rate, as well as overall survival. 2.To ask for subgroups that show the greatest benefit from conventional chemotherapy and 3. to ask for impact of guidelines violation on RFS and OA. Patients and methods: 3658 breast cancer Patients that were first diagnosed between the years 2000 and 2005 were analyzed in a multicentric retrospective study. A total of 371 (10,1%) were triple negative. Results: Median age was 62 years(26-101) TN: 60years.(28-97). 13,8% of all included patients are triple negative. 90,3% of all TN patients are at intermediate/high risk according to Nottingham risk classification. 76,5 have G3 tumors. The 5 year DFS is 74,8% (95%CI 68,8% - 80,8%) and for none TN 86,5%(95%CI 84,6% - 88,4%) (logrankp<0,0001). The 5 year OS is 75,8%(95%CI:69,9%- 81,8%) and for none TN 86%(95%CI:84,1%-87,9%). (logrank p < 0,0001). The essential parameters for RFS and OS were guidelines conforming surgery and radiation therapy, when chemotherapy conforming to guidelines was provided. The 5 year RFS for TN patients undergoing a 100% guideline according adjuvant therapy is 86.1%(95%CI:78.9%-93.4%), with 1-2 violations 76.0% (95%CI:69.0%-83.1%) and with ≥3 violations 50.6%(95%CI:20.1%-81.1%) (logrank p<0.0001). In total a 66,8% of all TN patients were not treated according to guidelines (ranking of violations: Chemotherapy, radiation therapy, surgery). 18% had 2 or more violations. Summary: The Results show a significant improvement of outcomes in TN breast cancer patients when treatment is conducted in accordance to guidelines. There are subgroups of TN breast cancer patients that profit from therapy according to guidelines. The leading guideline violation was noted for radiation therapy.
Bone Mets/Pain Stabilizes over Time with Proper Management
[2051] The Incidence of Bone Metastases and Skeletal-Related Events in Breast Cancer Patients: A Population-Based Cohort Study in Denmark (1999 – 2007). Yong M, Jensen AØ, Jacobsen JB, Nørgaard M, Fryzek JP, Sørensen HT Amgen Inc., Thousand Oaks, CA; Aarhus University Hospital, Århus C., Denmark Background Breast cancer (BrCa) is the most commonly diagnosed cancer among women in the industrialized world. More than half of women presenting with metastatic BrCa develop bone metastases. Bone metastases increase the risk of skeletal-related events (SREs), defined as radiation to bone, pathologic fractures, spinal cord compression, bone surgery, or altered antineoplastic therapy to treat bone pain. Both bone metastases and SREs are associated with unfavorable prognosis and greatly affect quality of life. To date, the epidemiology of the subgroup of BrCa patients who develop bone metastases and/or SREs has not been well-characterized. Our objective was to estimate the one- and five-year incidence of bone metastases and SREs in a large population cohort of newly-diagnosed BrCa patients in Denmark (population ~ 5.4 million inhabitants). Methods We identified women diagnosed with BrCa (International Classification of Diseases, 10th Revision (ICD-10) code C50.x.) from January 1, 1999 through December 31, 2007, with follow-up through April 2008. We retrieved this data from Denmark's National Registry of Patients (NRP), which includes records from all Danish hospitals. We also identified bone metastases (ICD-10 code C79.5) and recorded SREs. The Kaplan-Meier method was used to estimate time to bone metastases and time to first SRE. We also calculated 1- and 5-year incidence rates (IR) of bone metastases and first SRE in newly-diagnosed BrCa patients. Results We identified 35,941 BrCa patients from the NRP. The median age at diagnosis was 62 years (range, 18-104 years). A total of 1,494 (4%) patients developed bone metastases during follow-up, and of these, 712 developed an SRE. The distribution of SREs by type were 394 (55%) with radiation to the bone, 133 (19%) with pathological or osteoporotic fracture, 42 (6%) with bone surgery, and 143 (20%) with spinal cord compression. The 1-year IR of bone metastases was 13.7 [95% confidence interval (CI): 12.5-15.0] per 1000 person-years (P-Y). The 1-year IR of SREs among patients with bone metastases was 55 times that of the 1-year IR of bone metastases in BrCa patients at 759.2 (95% CI: 662.0-870.5) per 1000 P-Y. After five years of follow-up, the incidence curves plateaued at approximately 4% and 48% for bone metastases and SREs, respectively (Figures 1 and 2). Conclusions Among breast cancer patients with bone metastases, there was a strong tendency towards development of SREs within a year of bone metastases diagnosis; however, this phenomenon stabilized beyond 5 years of bone metastases diagnosis.
Curcumin to the Rescue!
[3098] Curcumin Modulates Tamoxifen Response in Resistant Breast Cancer Cells. De Gasperi MJ, Cavazos D, deGraffenried LA University of Texas at Austin, Austin, TX Despite significant improvement in both detection and treatment, breast cancer remains the second leading cause of cancer deaths for women in the United States. Tamoxifen is the most commonly used treatment for estrogen receptor positive (ER+) breast carcinoma, yet up to 50% of patients with metastatic disease present with de novo resistance to tamoxifen, and almost all patients will eventually become resistant to tamoxifen treatment. The mechanism(s) for this resistance appear to be largely dependent upon activation of growth factor signaling pathways. Aberrant activation of the PI3K/Akt and MAPK pathways and their cross talk with both the genomic and nongenomic activity of the ER is implicated in tamoxifen resistance. Breast cancer cell lines with constitutively activated Akt are characterized by high levels of the pro-survival transcription factor Nuclear Factor kappa B (NF-kB), estrogen-independent growth, and resistance to tamoxifen treatment. Studies have shown that curcumin, a polyphenol derived from the rhizome of the perennial herb Curcuma longa, is able to inhibit the activation of NF-kB, which is implicated as one mechanism by which breast cancer cells become resistant to tamoxifen treatment. Previous studies in our laboratory have demonstrated that inhibition of NF-kB is sufficient to sensitize MCF-7 cells that have constitutively activated Akt and elevated NF-kB levels to tamoxifen treatment. However, clinical NF-kB inhibitors such as Velcade generally involve suppression of the proteosome, leading to severe toxicities. Therefore, identification of alternative approaches for suppressing NF-kB activity in the absence of toxicity could prove beneficial for enhancing response to tamoxifen. In the present study, we assessed the efficacy of curcumin at inhibiting breast cancer cell proliferation and survival both as a single agent and in combination with tamoxifen in MCF-7 cells that expressed both “normal” levels of Akt (Control) activity as well as those that expressed the constitutively active form of Akt (myrAkt). As has been previously reported, curcumin treatment inhibited survival and proliferation in the Control MCF-7 cells, but importantly curcumin was also able to suppress survival and proliferation in the myrAKT MCF-7 cells. Curcumin and tamoxifen co-treatment was found to synergistically inhibit survival in myrAKT MCF-7 cells. These findings demonstrate that curcumin can sensitize myrAKT MCF-7 cells to tamoxifen treatment. This preliminary data suggests that the combination of natural NF-kB inhibitors such as curcumin with tamoxifen may be a viable strategy to either prevent tamoxifen resistant disease or to re-sensitize refractory disease to tamoxifen treatment.
Gemzar and Carboplatin= Great Combo for Mets
[2105] Three-Year Follow-Up of Survival and Progression in a Phase II Trial of Gemcitabine Plus Carboplatin (Plus Trastuzumab in HER2+ Patients) in Metastatic Breast Cancer Patients. Loesch D, Asmar L, McIntyre K, Orlando M, Zhan F, Boehm KA, O'Shaughnessy J US Oncology Research, Inc., The Woodlands, TX; Central Indiana Cancer Centers, Indianapolis, IN; Texas Oncology, P.A., Dallas, TX; Eli Lilly and Company, Indianapolis, IN; Texas Oncology at Baylor - Charles A. Sammons Cancer Center, Dallas, TX Background: We have previously reported (Loesch, et al. Clin Breast Cancer, 2008) the efficacy and safety of gemcitabine and carboplatin with or without trastuzumab in patients with metastatic breast cancer. We now report time-to-progression (TTP) and overall survival (OS) after up to 3.5 years of extended follow-up. Patients and Methods: Patients were stratified into 3 groups at registration; Group 1: HER2 positive (+) regardless of prior taxane; Group 2: HER2 negative (–) and taxane naïve or remote (no taxanes within the past 2 years); and Group 3: HER2– and taxane pretreated. Women ≥18 years of age, with ECOG performance status 0-2, with RECIST-defined measurable disease, and either HER2– or HER2+ (3+ score) by immunohistochemistry or fluorescence in situ hybridization were enrolled. Treatment: Day 1 gemcitabine 1500 mg/m2 over 30 minutes followed by carboplatin AUC=2.5 repeated every 14 days up to Cycle 9. Group 1 also received trastuzumab 8 mg/kg in Cycle 1 followed by 4 mg/kg in Cycles 2-9, followed thereafter by 6 mg/kg every 21 days until progression or intolerable toxicity. Results: A total of 150 patients were registered (50, 51, and 49 in Groups 1, 2, and 3, respectively). Median follow-up for surviving patients, calculated from registration, was 31.3, 27.1, and 25.4 months, respectively. Median TTP (calculated as progression-free survival), was 7.2, 5.6, and 4.6 months, respectively. Median OS (range) has not been reached for Group 1 (range, 1.2-46.9); for Group 2 was 21.7 months (<1-44.3); and, for Group 3 was 11.9 months (<1-33.6). At 24-months, survival rates were 73.3%, 41.4%, and 20.5%, respectively; at 36-months, survival rates were 60.6%, 25.7%, and ≤8.3%, respectively. For Group 1 only, the remaining 3 responding patients were followed for 3.5 years, at which time they were relapse-free. Conclusions: Gemcitabine plus carboplatin with or without trastuzumab has been shown to be highly active in metastatic breast cancer. HER2+ patients receiving trastuzumab had the highest TTP and survival rates of all treatment groups. As expected, taxane-pretreated patients had shortened TTP and decreased OS rates compared to taxane-naïve patients. Research support was provided, in part, by Lilly USA, LLC; Indianapolis, IN.
Great First Line Metastatic Treatment News
[2099] Superiority of Docetaxel + Capecitabine Compared to Docetaxel + Epirubicin as First-Line Therapy for Metastatic Breast Cancer – Final Results of the ERASME-4 Study. Bachelot T, Bajard A, Ray-Coquard I, Provencal J, Coeffic D, Dramais D, Ferri-Dessens R-M, Guastalla J-P, Perol D Centre Léon Bérard, Lyon, France; Centre Hospitalier, Annecy, France; Institut Daniel Hollard, Grenoble, France; Centre Hospitalier, Valence, France; Roche France, Paris, France Background: Docetaxel plus capecitabine (DC) combination therapy improves both time to disease progression and overall survival over docetaxel alone in metastatic breast cancer (MBC). The aim of the ERASME-4 trials was to assess the efficacy of DC vs. docetaxel plus epirubicin (DE) combination regimens as first-line therapy for MBC. Material and Methods: Patients with MBC, previously untreated with chemotherapy were randomly assigned to receive either DC (docetaxel 75 mg/m² on day 1 and oral capecitabine 1,000 mg/m² twice daily on days 1 to 14 every 3 weeks) or DE (docetaxel 75 mg/m² and epirubicin 75 mg/m² on day 1 every 3 weeks). The primary endpoint was progression-free rate 6 months after randomization. The planned sample sizes were 106 patients (pts), based on a randomized phase II selection design. The main secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Between June 2004 and April 2006, 68 pts were randomized. Slow accrual led to premature termination the study. Final analysis included 33 pts randomized to DC and 35 pts to DE. This sample size allowed to effectively selecting the best arm for non-progression rate with a power of 82%. Patient characteristics were well balanced between the two treatment arms, except for pleural metastasis, alkaline phosphatase and SBR III more present in DE arm or adjuvant hormonotherapy given in more DC patients. Toxicity has been mild or moderate; 62% of patients reported at least one grade 3-4 episode. Hand-foot syndrome grade 3-4 was reported for 18% of DC arm patients, vs. none in the DE arm (p=0.008). Complete/partial response rates were 20/44% in DC and 7/41% in DE (p=0.3). Six months after randomization, 75.8% (95%CI: 57.7-88.9) of pts in the DC arm vs. 65.7% (95%CI: 47.8-80.9) in the DE arm were progression-free (p=0.36). After a median follow-up of 42 months, (95%CI: 32.5-21.1), median PFS was 12 months and 7 months in the DC and DE groups, respectively (p=.004). Median OS was 27 and 37 months for DE and DC respectively (p=0.49). Conclusion: Despite our low accrual, these results show that DC combination therapy is associated with a superior progression-free rate at 6 months and a longer PFS than DE. DC provides a highly active, non-anthracycline-containing, first-line treatment option for MBC patients previously exposed to anthracycline in the adjuvant setting.
IXEMPRA GOOD NEWS for TNBC
[2097] Clinical and Pharmacokinetic Study of Ixabepilone (IXA) Plus Epirubicin (EPI) as Therapy for Women with Advanced Breast Cancer (BC). Gianni L, Dalenc F, De Benedictis E, Gladieffe L, Zambetti M, Mudenda B, Iacono L, Parker S, Roche H Istituto dei Tumori, Milan, Italy; Centre Claudius Regaud, Toulouse, France; Bristol-Myers Squibb, Wallingford, CT; Bristol-Myers Squibb, Lawrenceville, NJ Background: IXA and EPI have established single agent activity in early and late stage BC, however, safety and pharmacokinetics (PK) of the combination are unknown. This study aimed to determine the dose-limiting toxicities (DLT), define the maximum tolerated dose (MTD), investigate PK, and evaluate safety and activity of the combination of IXA and EPI in women with advanced BC. Patients and Methods: Women with locally advanced, recurrent or metastatic BC with ≤ 1 prior chemotherapy regimen as 1st line therapy, a maximum cumulative dose of ≤ 450 mg/m2 for EPI, or ≤300 mg/m2 for doxorubicin were eligible. A short IV infusion of EPI was followed by a 3-hour IV infusion of IXA given every 3 weeks. Three cohorts (3 to 6 patients (pts) per cohort) received IXA/EPI at 25/75, 30/75 and 35/75 mg/m2 respectively. An additional 24 pts were enrolled at the MTD. Blood samples for PK analysis of IXA, EPI and epirubicinol (EOL, major metabolite of EPI) were collected from all pts during cycle 1 and analyzed using LC/MS/MS. PK samples were collected out to 120 h for ixabepilone and 24 h for EPI/EOL. PK parameters were generated by non-compartmental methods. Results: Forty-two pts, median age of 57 (33-69) yrs were treated, 6 at 25/75 mg/m2, 6 at 35/75 mg/m2 and 30 at 30/75 mg/m2, receiving a total of 249 cycles (median 6, range 1-10). All pts were evaluable for safety and efficacy and 38 were evaluable for PK. Two DLTs, febrile neutropenia and grade 3 vomiting, occurred at the 35/75 mg/m2 dose level; therefore 30/75 mg/m2 (IXA/EPI) was defined as the MTD. No deaths or grade 4 non-hematological toxicities were reported. Neutropenia was the most frequent treatment related severe toxicity. Objective responses were seen at all dose levels in 18/32 pts (56%) with measurable disease. In addition, 2/10 pts (17%) with non-measurable disease had complete response. PFS was ≥6 mo in 27 (64%) pts and ≥ 9 mo in 18 (43%). IXA plasma concentrations declined rapidly in the first 24 hrs, followed by a slower elimination phase. Observed means of both elimination half-life (34-52 h) and clearance (25-27 L/h) within each cohort indicate a slow elimination of IXA from plasma. The IXA Cmax and AUC were linear across the 3 dose levels evaluated. With the EPI dose remaining at 75mg/m2, no alteration in EPI AUC was observed across dose levels. Exposure to EOL decreased with increasing IXA dose (Geo Mean AUC: 575.48, 314.46 and 204.46 in each dose group respectively). This may be due to altered metabolism of EPI in the presence of IXA or Cremophor in the IXA formulation. No relationship was observed between PK parameters of IXA, EPI or EOL and nausea, vomiting, and neutropenia. Conclusions: The combination of IXA/EPI is feasible, efficacious and has an acceptable safety profile at the studied dose levels. No clinically relevant PK interactions were observed. The observed effect on EOL exposure deserves further investigation.
Lymphedema Increases Over Time
[2070] Occurrence of Lymphedema Continues To Increase Twelve to Thirty Months after Breast Cancer Treatment. Armer JM, Stewart BR, Shook RP University of Missouri, Columbia, MO Introduction: Breast cancer (BC) survivors are at lifetime risk for developing lymphedema (LE), the accumulation of protein-rich fluid in the interstitial spaces of the affected body part due to a blockage or malfunction in the lymph system. This is different than swelling which may occur immediately after surgery and may be present at the post-op visit, and the physical and psychological aspects of the condition greatly impact the daily lives of LE patients (Geller et al., 2003, Hull, 1998). Of those affected by breast cancer, up to 40% will develop LE, potentially comprising 1 to 5 million survivors. However, all breast cancer survivors are considered at risk for the condition (American Cancer Society, 2007). While numerous studies have reported LE incidence during the first 12 months following breast cancer treatment, little is known regarding long-term LE diagnosis. Very few studies have examined LE incidence past 1 year post-treatment, and many that have are retrospective or cross-sectional, not prospective, in nature. In fact, in one analysis of existing literature the study with the shortest follow-up (12 months) reported the lowest LE incidence (Ball et al., 1992) and the study with the longest follow-up (11 years) reported the highest incidence (Schunemann and Willich, 1997). Methods: Participants were enrolled following diagnosis of BC but before treatment and followed every 3 months for 12 months, then every 6 months until 2.5 years post-surgery. Limb volume changes (LVC) were measured using: (a) circumferences via tape measure at 4 cm intervals, (b) infra-red laser perometry, and (c) symptom experience (SS) via interview. Four diagnostic criteria for LE were used: (i) 2 cm circumferential change; (ii) 200 mL perometry LVC; (iii) 10% perometry LVC; and (iv) report of limb heaviness/swelling, 'now' or 'in the past year'. Standard survival analysis methods were applied to identify when the LE criteria were met. Results: At 30 months post-treatment, LE incidence using the four criteria ranged from 41%- 91% and had continued to increase over time, with 2 cm being the highest estimation method and SS the lowest. Conclusions: These preliminary findings provide additional evidence that BC survivors continue to be at risk for developing LE beyond the first year following treatment. LE identification, regardless of the criteria used, continued to increase past the initial 12 months post-treatment. From month 12 to month 30, LE identification increased by an additional 10-27%, depending on the criteria used. While identification of LE via symptom experience in the initial 12 months occurred in 31% of participants, only an additional 10% met the criteria at 30 months, by far the lowest incidence rate among all criteria. Overall, this analysis finds 2 cm criteria as the most liberal definition of LE (91%), while self-report of heaviness and swelling, along with 10% LVC, represent the most conservative definitions (41% and 45%, respectively).
Lobular? Ductal? No Difference in the End
[2046] Outcome of Invasive Lobular Carcinoma Compared to Infiltrating Ductal Carcinoma: A Population Based Study from British Columbia. Al-Foheidi M, Speers C, Woods R, Kennecke H, Chia SK British Columbia Cancer Agency, Vancouver, BC, Canada Background: Lobular carcinoma is the 2nd most common invasive breast cancer histology after ductal carcinoma. Though phenotypically they are different, the two histologies are often treated the same with presumed similar outcomes. We sought to compare the baseline demographics, standard pathologic factors and long term clinical outcomes between lobular and ductal carcinoma from a large population based breast cancer registry. Methods: A retrospective cohort of referred patients to the BCCA with a diagnosis of stage I-III pure lobular or pure invasive ductal carcinoma from 1989-2000 was identified. Prior or synchronous breast cancers and cases with unknown grade were excluded. Standard demographic and pathologic factors was abstracted from the BCCA Breast Cancer Outcomes Unit database and compared between the two histologies. 10 year outcomes were calculated by Kaplan Meier method, with differences compared by log rank test. Median follow up for the entire cohort was 9.3 years. Results: A total of 13,203 individual patients meeting identified inclusion criteria were identified: 11,911 invasive ductal and 1,292 invasive lobular cancers. Lobular carcinomas generally had a higher frequency of poor prognostic factors: older age (≥ 70 years old), larger tumour size, and greater frequency of N2 nodal involvement (all p<0.001). However lobular carcinomas also had a higher frequency of better predictive factors: ER+ status and low grade tumours (both p<0.001). There were differences in locoregional treatments and systemic therapies between the groups. No differences were seen at 10 year estimated relapse free survival (76% vs 74%), distant RFS (78% vs 77%), breast cancer specific survival (81% vs 81%) and overall survival (69% vs 70%) between lobular and ductal cancers respectively. Only 10 year locoregional RFS significantly favored lobular cancers (93% vs 89%; p<0.001), though there was also a higher mastectomy rate (55% vs 39%) in this cohort. Conclusion: Though invasive lobular carcinomas are epidemiologically and phenotypically different from ductal carcinomas, clinical outcomes are comparable between these two common histologies.
Blood Cancer Risk Post Breast Cancer Treatment
[2082] Myelodysplastic Syndrome and Acute Myeloid Leukemia Incidence Following Primary Breast Cancer Treatment. Kaplan HG, Malmgren JA, Atwood MK Swedish Cancer Institute, Seattle, WA; HealthStat Consulting, Inc., Seattle, WA Background: Breast cancer (BC) patients receiving surgery plus radiation and/or adjuvant chemotherapy treatment are routinely monitored for incidence of myelodysplasia (MDS) and leukemia. Methods: A cohort of all breast cancer patients TNM stage 0-III treated with surgery and/or radiation or chemotherapy from 1989 to 2005 at our institution were followed for incidence of blood disorders of any type by our registry system and by linkage to the Surveillance, Epidemiology and End Results registry (SEER) for our area. Cases without surgery (n=111), with stem cell transplantation (n=98), unknown or non-standard chemotherapy regimens (n=23 + 71= 94), lost to follow up (n=66) or cancer status unknown at follow up (n=67) were excluded. The remaining 5790 cases were reviewed for incidence of leukemia including MDS and acute myelogenous leukemia (AML) post breast cancer treatment by chart review including pathology reports, SEER coding for MDS/AML, and death certificates if appropriate. Mean length of follow up was 7.17 years, range 2-18 years. Results: The mean age of MDS/AML patients was 57 years, range 33-76 years. The crude rate of MDS/AML occurrence was .29% (17/5790). 17 cases of MDS/AML (10 MDS/7 AML) occurred during the follow up period as compared with 6.22 (4.03 MDS/2.19 AML) expected on the basis of rates in the general population by age <65, ≥ 65 years calculated from SEER registry data (risk ratio (observed/expected)). The risk of MDS in women <65 was 11.68 times that expected and the risk of AML in women <65 was 9.2 times the expected rate. Risk among women over 65 was not as large (1.38 MDS, ≥ 65, 1.21 AML, ≥ 65). Average time from treatment with radiation or chemotherapy to MDS diagnosis was 5.50 years (range 1.03-12.95) and 3.42 years (range .41-6.84) for AML. The majority of MDS/AML cases occurred in the first five years post treatment (n=10) with 7 more cases observed from 5 to 12.95 years (see figure). Initial treatment of MDS/AML patients was surgery only (n=2), surgery/chemotherapy (n=1), surgery/ radiation (n=7), and surgery/chemotherapy/radiation (n=7). The two MDS patients who had initial treatment of surgery only were subsequently treated with chemotherapy and radiation for recurrence. Fifty percent of MDS patients (5/10) received surgery and radiation treatment without adjuvant chemotherapy treatment. Discussion: The incidence of MDS/AML is very small in this cohort but significantly greater than that expected in the population at large especially among women less than 65 years of age. A significant number of women who received radiation treatment without chemotherapy developed MDS post breast cancer treatment. Average time from treatment to MDS diagnosis exceeded the 2-5 year time period previously reported as an expected interval.
Great Results for Lymph Node Transplantation on Lymphedema
[3112] Lymph Node Transplantation in Breast Reconstruction Using Perforator Flaps. LoTempio MM, Studinger RM, Vaisille J, Chen C, Levine JM, Allen RJ NYU, NY, NY; Private, NY, NY Introduction: For many women undergoing breast reconstruction, the negative impact of upper extremity lymphedema outweighs the benefits of breast reconstruction. Patients with lymphedema present a challenging problem, and typically is not addressed during the reconstruction process. Lymph node dissections have decreased secondary due to the advent of the sentinel node biopsy. However, 7% of patients undergoing sentinel lymph node biopsy develop lymphedema. Previous treatments options have not proved to be highly successful, and include lymphatic massage and lymphaovenous anastomosis. We introduce a combined treatment for breast reconstruction using deep inferior epigastric perforator flap (DIEP) along with lymph node transplantation for lymphedema. Methods: Beginning in 2007, 23 patients have undergone bilateral breast reconstruction using the DIEP along with simultaneous lymph node transplantation. Each patient had demonstrated upper extremity lymphedema by measurements and subjective findings. Of the 23 patients 18 had radiation therapy and five had sentinel node dissection. The lymph node flap was harvested surrounding the superficial circumflex vessels in conjunction with the DIEP. The combined DIEP and lymph nodes were anastomosed to the internal mammary artery. Preparation of the axilla included removal of scar tissue, and fixation of the lymph nodes into the axilla. Results: Each patient had an uncomplicated postoperative course. These patients started to experience resolutions of lymphedema as early as ten days after surgery and continued up to six months. Currently, 15 patients no longer need lymphatic massage nor wear compression garment. One patient had a recurrence of breast cancer. Each patient reported their arm circumference had improved and decreased morbidity associated with lymphedema. Conclusion: Lymph node transplantation is a relatively new and exciting option for the management of lymphedema. Women who undergo breast reconstruction using perforator flaps can have simultaneous lymph node transplantation with minimal morbidity. These patients experienced an overall 89% improvement of symptoms.
Male Breast Cancer News
[2075] Male Breast Cancer: A Population-Based Comparison with Female Breast Cancer. Anderson WF, Jatoi I, Rosenberg PS National Cancer Institute, Rockville, MD; National Naval Medical Center, Bethesda, MD Purpose: Because of its rarity, male breast cancer is often compared to female breast cancer. Materials and Methods: To compare and contrast male and female breast cancers, we obtained case and population data from the NCI's Surveillance, Epidemiology, and End Results program for breast cancers diagnosed from 1973 through 2005. Standard descriptive epidemiology was supplemented with age-period-cohort models and breast cancer survival analyses. Results: Men with breast cancer comprised less than 1% of all breast cancers. Male compared to female breast cancers occurred later in life with higher stage, lower grade, and more estrogen receptor positive tumors. Recent breast cancer incidence and mortality rates declined over time for men and women, both overall and within each age group, but these trends were greater for women than men. Comparing cases diagnosed in 1996 through 2005 versus 1976 through 1985, and adjusting for age, stage, and grade, cause-specific hazard rates for breast cancer death declined by 28% among men (p = 0.03) and by 42% among women (p ~ 0). Conclusion: There were three intriguing results. Age-specific incidence patterns showed that the biology of male breast cancer resembled the late-onset and hormone sensitive type of female breast cancer. Similar breast cancer incidence trends among men and women suggested that there are common breast cancer risk factors that affect both sexes, especially hormone positive breast cancer. Finally, breast cancer mortality and survival rates have improved significantly over time for male breast cancer, but progress has lagged behind for men compared to women.
Docs need to do better job informing patients of Reconstruction Choices
[3103] Decisions about Breast Reconstruction after Mastectomy: Patient Involvement, Knowledge, and Preferences. Lee CN, Belkora J, Cosenza C, Chang Y, Levin C, Moy B, Partridge A, Sepucha K University of North Carolina, Chapel Hill, NC; University of California San Francisco, San Francisco, CA; Massachusetts General Hospital, Boston, MA; Dana Farber Cancer Institute, Boston, MA; Foundation for Informed Medical Decision Making, Boston, MA; University of Massachusetts Boston, Boston, MA Background: Most breast cancer patients who have a mastectomy do not have breast reconstruction, and rates of reconstruction vary by race, education, and geographic location, suggesting problems with decision making. We sought to assess the quality of decisions about breast reconstruction by measuring patient involvement in decision making, patient knowledge, and the degree to which decisions reflected patients' goals. Methods: Breast cancer survivors from four sites who were treated with mastectomy in the past 3 years completed a mailed survey, as part of a larger study to validate decision quality instruments. The survey contained questions about the decision making process, factual questions, and questions about personal goals and concerns. Characteristics associated with knowledge were identified with linear regression. Goals/concerns associated with reconstruction were identified using logistic regression. The percent match between treatment preference and treatment received was calculated. Results: The larger study recruited 456 patients (overall response rate 59%). 91 patients completed the reconstruction module. Average age was 56.9 years, 82.6% were white, 63.7% had a college degree, and 64% had Stage I disease. 45.8% had reconstruction. Decision making: 78% of patients reported that their doctor mentioned reconstruction. Most reported a discussion of the pros of reconstruction (63.8%), whereas the minority reported a discussion of the cons (20.9%). 76% reported being asked for their preference about reconstruction. 3% said the doctor mainly made the decision, 74% said they made the decision, and 15% said both made the decision. Most (81%) felt their level of involvement was about right. Knowledge: The mean knowledge score was 32.9% (SD=19). 41% knew that reconstruction has little effect on cancer surveillance. 54% knew that recovery after implant surgery is easier than after flap surgery. 3.3% knew that about 1/3 of patients have a major complication. On bivariate analysis, reconstruction (43.3 vs. 32.6, p=0.053), higher income (43.4 vs. 26.3, p=0.008), a college degree (43.4 vs. 26.2, p<0.01), and being married (40.9 vs. 29, p=0.04) were associated with higher knowledge. On multivariate analysis, higher income was associated with higher knowledge (p=0.0013). Preferences: The following goals were associated with reconstruction: “use your own tissue to make a breast” (OR 1.309, CI 1.028, 1.605), “avoid using a prosthesis” (OR 1.254, CI 1.039, 1.512), and “wake up after mastectomy with reconstruction underway” (OR 1.254, CI 1.057, 1.487). Patients who felt it was important to “avoid putting foreign material in your body” were less likely to have reconstruction (OR 0.682, CI 0.518, 0.899). The majority of patients (81%) had treatment that was concordant with preference. Conclusions: Despite reporting high involvement in decisions about reconstruction, breast cancer patients undergoing mastectomy had major knowledge deficits, and many reported having treatment they did not prefer. In addition to involving patients in decisions about reconstruction, surgeons should discuss both the pros and the cons and should explicitly ask patients for their preference about reconstruction.
MRI Finds more Tumors
[4018] Retrospective Study Assessing the Role of MRI in the Diagnostic Procedures for Early Breast Carcinoma: A Correlation of New Foci in the MRI with Tumor Pathological Features. Calvo Plaza I, Ugidos de la Verga L, Miró C, Suarez A, Perez P, Quevedo P, Parras M, Torres M, Herrero M, Buelga P, García L, Alonso P, de la Cruz JJ, López Ríos F, Hidalgo M, G Estévez L Centro Integral Oncológico Clara Campal, Madrid, Madrid, Spain; Autonoma University, Madrid, Madrid, Spain Purpose: To analyze the role of MRI in the detection of additional disease and the need to perform additional biopsies in early breast carcinoma patients. In addition, to correlate the detection of new foci with tumor pathological features. Methods: Early breast carcinoma patients that had undergone a MRI as well as a mammography as diagnostic procedures were included in the study. The following pathologic features were studied: carcinoma type, histological grade, estrogen (ER)/progesterone (PR) receptors, HER2 and Ki67. HER2 status was established by FISH, while ER, PR and Ki67 status were established by inmunohistochemistry. Univariate analysis was conducted to ascertain significant correlation among detection of new foci and each of the tumor pathological features. Results: To date, data from 98 patients have been analyzed: median age 49 years (range: 35-79); carcinoma type: a) infiltrative ductal carcinoma (n=73, 74%), b) infiltrative lobular cancer (n=13, 13%), c)ductal carcinoma in situ (n= 6, 6%); amplified HER2 (n=18, 18%); grade III (n=33, 33%);Ki67 ≥ 25%(n=33, 33%); positive ER and PR (n=78, 79%); triple negative tumors (n=8, 8%). MRI detected additional disease in 38 cases (39%) that led to an additional biopsy in 20 cases (20%). Thirty-nine patients (39%) underwent mastectomy. A statistically significant correlation was established between the finding of new foci in MRI and high proliferative tumors through the biomarker Ki67 (cutoff ≥ 25%) (p<0.005). No other statistically significant correlation was established with any of the other pathological features analyzed. Conclusion: In patients diagnosed with early breast cancer, MRI detected the presence of additional disease in 39% of the cases, requiring an additional biopsy in 20% of the cases. Tumors with high proliferative index were significantly correlated with the detection of new foci in MRI. An update of the results will be presented at the symposium.
Amazing Promise for PARP in TNBC
[3122] Final Results of a Randomized Phase II Study Demonstrating Efficacy and Safety of BSI-201, a Poly (ADP-Ribose) Polymerase (PARP) Inhibitor, in Combination with Gemcitabine/Carboplatin (G/C) in Metastatic Triple Negative Breast Cancer (TNBC). O'Shaughnessy J, Osborne C, Pippen J, Patt D, Rocha C, Ossovskaya V, Sherman B, Bradley C Baylor Sammons Cancer Center, Dallas, TX; Texas Oncology, Dallas, TX; Texas Oncology Cancer Center, Austin, TX; US Oncology, Dallas, TX; BiPar Scienes, Inc., South San Francisco, CA Background: TNBC is an aggressive breast cancer subtype which shares molecular and pathologic features with BRCA1-related breast cancers. BRCA-deficient cells are sensitive to inhibition of PARP1, a critical enzyme of cell proliferation and DNA repair, and thus represent a rational target of PARP inhibitor-based cancer therapy. The objectives of this study were to evaluate BSI-201, a potent PARP1 inhibitor, in combination with G/C in subjects with metastatic TNBC. Methods: Eligible subjects had measurable disease and received ≤2 prior cytotoxic regimens for ER-, PR-, and HER2-negative metastatic breast cancer. Patients were randomized (1:1) to G/C alone or G/C + BSI-201. Gemcitabine (1000 mg/m2; IV) and carboplatin (AUC = 2; IV) were given on days 1 and 8, and BSI-201 (5.6 mg/kg; IV) on days 1, 4, 8, and 11 every 21 days. Endpoints were clinical benefit rate (CBR = CR + PR + SD ≥6 months), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Preliminary analyses of all 116 dosed patients showed that, based on all patient visits through March 2009, BSI-201 + G/C improved CBR, ORR, median PFS, and median OS, compared with G/C alone. The frequency and nature of adverse events did not differ between arms. Conclusions: This analysis demonstrates that BSI-201 + G/C improved patient's outcomes, as measured by CBR, ORR, PFS and OS, compared with G/C alone. BSI-201 + gemcitabine/carboplatin was well tolerated and did not potentiate chemotherapy-related toxicities. Final data on CBR and ORR, as well as updated analyses of PFS and OS for all 116 dosed patients will be presented based on all patient visits through September 2009. Exploratory correlative analyses of PARP expression and overall clinical response will also be presented, as well as initial correlative analyses between number of metastatic therapies and clinical response.
Patient Preferences Important in Chemotherapy Choices
[2083] The Quality of Decisions about Adjuvant Chemotherapy for Early Stage Breast Cancer. Lee CN, Belkora J, Wetschler M, Chang Y, Feibelmann S, Moy B, Partridge A, Sepucha K University of North Carolina Chapel Hill, Chapel Hill, NC; Massachusetts General Hospital, Boston, MA; University of California San Francisco, San Francisco, CA; Dana Farber Cancer Institute, Boston, MA Background: Decisions about adjuvant chemotherapy are highly challenging for many women with early stage breast cancer. We sought to assess the quality of breast cancer patients' decisions about chemotherapy by measuring their knowledge and the degree to which their treatment decisions reflect their goals and preferences. Methods: We mailed a survey to early stage (I, II) breast cancer survivors who were treated at one of four sites, as part of a larger study to validate decision quality instruments. A subset of women completed the chemotherapy module, which included questions about the patient-provider interaction, about facts, about treatment goals, and about the patient's preferred treatment. Characteristics associated with knowledge were identified with linear regression. Characteristics associated with chemotherapy were identified with logistic regression. The percentage of patients who received their preferred treatment was calculated. Results: 358 patients completed the survey (response rate 59%). 64% of patients had Stage I disease, and 57% had chemotherapy. Average age was 56.9 years, 82.6% were white, and 63.7% had a college degree. Decision making: 70% of patients reported that their provider mentioned chemotherapy as an option. 43% reported that their provider asked for their preference about chemotherapy. 23% said the doctor mainly made the decision, 29% said they mainly made the decision, and 46% said both made the decision. Most women (92%) felt their level of involvement was about right. Knowledge: The mean knowledge score was 39.6% (SD 20.3). 29.9% knew that less than half of women with early stage breast cancer eventually die from breast cancer without chemotherapy or hormone therapy. 21.8% knew that more than half are free from recurrence in 10 years without chemotherapy or hormone therapy. Chemotherapy treatment and the doctor having discussed chemotherapy were significantly associated (p<0.05) with higher knowledge. Younger age at diagnosis, white race, higher income, and a college degree were also significantly associated with higher knowledge (p<0.05). Treatment: Factors associated with having chemotherapy were younger age (OR 1.71, 95% CI 1.01, 2.91) and not having hormone therapy (OR 3.2, 95% CI 1.92, 5.42). Factors associated with not having chemotherapy were lower stage (OR 0.17, 95% CI 0.10, 0.30), mastectomy (OR 0.47, 95% CI 0.26, 0.86), and the goal “live as long as possible” (OR 1.41, 95% CI 1.10, 1.80). Concordance with preferences: 81.6% of patients who preferred chemotherapy received it, and 92.6% of patients who preferred no chemotherapy received no chemotherapy. Conclusion: Breast cancer patients had substantial knowledge deficits about chemotherapy, which were even more prevalent among older, non-white, less educated, and lower-income women. In addition, more than half of women reported they were not asked about their preferences, and some reported getting chemotherapy treatment that was not concordant with their preferences. Oncologists should address knowledge deficits and explicitly ask patients their preferences.
Safety in Long Term Outcome if you Get Pregnant post Treatment
[2062] Pregnancy after Breast Cancer in Young Patients Does Not Worsen the Outcome of Breast Cancer. Cordoba O, Sabadell MD, Rubio IT, Cortadellas T, Xercavins J Hospital Vall d'Hebron, Barcelona, Spain Background: Pregnancy after breast cancer may worsen the outcome of breast cancer due to associated hormonal changes, especially among young patients. However, prior studies have failed to detect this effect, which may be explained by the selection of patients of older age and those that gave birth to term. The aim of this study is to assess the effects of pregnancy on the outcome of breast cancer in young patients. Patients: One hundred twenty three young patients (≤35 years) with invasive breast cancer or ductal carcinoma in situ treated consecutively at our hospital between 1995 and 2005. Pregnancy was discouraged during the first two years, but not specific recommendation was given thereafter. Methods: We compared the prognostic factors, treatment with adjuvant chemotherapy treatment and follow-up between patients with pregnancy after breast cancer (P) and those who have not had subsequent pregnancy (NP). Results: There were 20 patients that get pregnant (16%). Of them, eight (40%) decided to interrupt pregnancy, and twelve (60%) gave birth to the term. The average time between diagnosis of cancer and pregnancy was four years. Several prognostic factors, such as age at diagnostic (median age 31 years old in both groups), histological type (CDI in P81% NP83.2%), clinical stage(P: 0 9.5%, I 38.1%, IIA 42.9%, IIIA 9.58%; NP: 0 7.9%, I 23.8%, IIA 32.7%, IIB 16.8%, IIIA 8.9%, IIIB 5.9%, IV 1%), positive axillary lymph nodes (P: 44.4% NP: 51.7%), histological high grade (P: 52.9% NP: 50.6%) and use of chemotherapy (P:76.2 NP: 89.2%) were similar among pregnant and non-pregnant women with differences who was not stadistical significance. However, use of hormonal treatment were more frequent in patients without later gestation (P: 33.% NP 68% p=0.003). Ductal Carcinoma in situ is more frequent among patients wit pregnancy but the difference is not statistical significant (P: 14% NP 4% p=0.10). Patients with pregnancy had better disease-free interval at 5 years (P95% vs NP62% p = 0.003) and overall 5 years survival(100% vs. 82% p = 0.008). Conclusions: A significant proportion of patients diagnosed of breast cancer at young age get pregnant, many of them unwillingly. Our study shows that pregnancy does not seem to worsen outcome. Patients should be counselling do not discontinuing her pregnancy.
Response Rate lower in BRCA1 Patients treated with Taxanes
[2098] Sensitivity to Taxane Chemotherapy for Metastatic Breast Cancer in BRCA1 and BRCA2 Mutation Carriers Compared to Sporadic Breast Cancer Patients. Seynaeve C, Jager A, Hooning M, den Bakker M, Bontenbal M, Blom J, Collee M, van den Ouweland A, Kriege M Erasmus MC - Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; Erasmus MC, Rotterdam, The Netherlands Purpose: Data of in vitro and small retrospective studies suggest that breast cancer (BC) (cells) without functional BRCA1 or BRCA2 protein have an increased sensitivity to chemotherapeutic agents causing double strand DNA breaks, while sensitivity to spindle poisons, such as paclitaxel and docetaxel, has been found to be decreased. Clinical data on the latter, however, are very scarce. In this study, we assessed the sensitivity to taxane chemotherapy for metastatic BRCA1/2-associated compared with sporadic breast cancer. Methods: From the family cancer clinic database, we retrieved 36 BRCA1 and 13 BRCA2-associated BC patients treated with taxane chemotherapy for metastatic disease before October 1, 2008, and with available data on follow-up and response assessment. Objective response (OR), and progression-free survival (PFS) after start of taxane chemotherapy were compared with those of 62 sporadic patients with comparable age at diagnosis and year of detection of metastatic BC. A t-test or chi-square test was used to test for differences in characteristics and response types, and Kaplan-Meier survival analysis to calculate PFS. Results: Taxane chemotherapy consisted of docetaxel (n= 76) or paclitaxel (n=21), while 10 (9%) patients received a taxane/trastuzumab regimen. It was given as first-line palliative therapy in 9 BRCA1, 1 BRCA2 and 22 sporadic patients; but mainly as second/third line treatment (BRCA1 n=27, BRCA2 n=12, sporadic patients n=40, respectively). As compared to sporadic patients, BRCA1-associated patients had a significantly lower OR rate (ORR) overall (22% vs 46%, p<0.001) and to 2nd/3rd line taxane treatment (19% vs 46%, p<0.001). Median PFS was shorter in BRCA1 patients (2.0 vs 4.1 mo, p=0.08), with a trend for significance for 2nd/3rd line therapy (1.6 vs 3.9 mo, p=0.05). Also, compared to BRCA2 patients, the ORR in BRCA1 patients was significantly lower, overall as well as to 2nd/3d line therapy (both p=0.003). In BRCA2 mutation carriers compared to sporadic patients, the ORR was higher (75% vs 48%, p=0.28) and PFS longer (6.4 vs 4.1 mo, p=0.33). After exclusion of the patients receiving a taxane/trastuzumab schedule, similar data were observed. Conclusion: Objective response rate to taxane chemotherapy for metastatic disease is lower in BRCA1-associated BC in comparison with sporadic as well as BRCA2-associated BC, resulting in a shorter PFS. If confirmed, these data may have substantial clinical relevance.
Seromas may spread cancer cells post surgery
[3146] Wound Fluid Induces Cancer Cell Growth: A Mechanism for Recurrence? Adelson K, Bahadur U, Halpern M, Hauptman E, Barginear M, Bleiweiss I, Ting J, Weltz C, Coomer C, Raptis G, Germain D Mount Sinai Medical Center, New York, NY Background: The process of wound healing after surgical resection of breast cancer may contribute to the development of local recurrence and possibly even metastases. Local recurrence after lumpectomy or mastectomy occurs most frequently near the surgical scar, leading to the hypothesis that the wound itself may promote the growth of residual disease. Some studies even suggest that removal of the primary tumor can accelerate progression of occult metastases. Two studies have shown that wound fluid can stimulate the growth of cancer cells and that differing cancer cell lines may be stimulated by differing wound fluid. A major criticism of these studies is that the activity of the wound fluid was compared to either the patient serum, which is likely less inflammatory than the wound fluid, or to serum free media. Thus, these studies did not define whether the inflammatory component of wound fluid alone is sufficient to stimulate cancer cell growth or whether the ability was specific to breast derived wound fluid. In this pilot study wound fluid was collected from 10 patients who had undergone unilateral mastectomy with abdominal flap reconstruction or bilateral mastectomy where one breast had known cancer and the contralateral did not. In the unilateral mastectomy patients, the fluid from the involved breast was compared to the fluid from the abdominal drain. In the bilateral mastectomy patients the fluid from the breast with cancer was compared with the fluid from the prophylactically removed breast. The effect of wound fluid on the growth of breast cancer cells was analyzed for each patient. Methods: Fluid from each breast and abdominal drain were collected 24 and 48 hours after surgery and their ability to promote growth of 6 different breast cancer cell lines was tested. In addition, the ability of the 48 hour wound fluid to stimulate colony formation of HBL-100 cells (ER-) on matrigel was established. The cytokine profile of the different wound fluid was also analyzed. Results: We found that when the ER – cells were cultured on matrigel, the breast derived fluid led to growth of invasive, branching colonies, while abdominal fluid from the same patient led to small round colonies. Further, we found that wound fluid derived from the breast where a tumor was present led to the formation of more invasive colonies than the wound fluid derived from the normal breast. Thus, we speculate that in addition to the normal cytokines and matrix metalloproteases associated with inflammation, breast wound fluid may contain additional proteins from the tumor bed microenvironment. In support of this model, we found that the protein composition of wound fluid varies from one site to another in the same patient. Conclusion: The biological activity and protein composition of wound fluid from the breast and abdomen is drastically different—such that breast wound fluid promotes growth and invasion of breast cancer cells. Thus, we hypothesize that residual disease may be stimulated to grow during the window of time after surgery when the wound fluid is produced. This transient stimulation may result in local recurrence if the nature of the residual disease is a foci cancer or acceleration of metastasis if the residual disease is disseminated into the surrounding lymph nodes or blood vessels.
Topical Estrogen May be Dangerous to women on AIs
[806] Effects of Vaginal Estrogens on Serum Estradiol Levels in Postmenopausal Breast Cancer Survivors Taking an Aromatase Inhibitor or a Selective Estrogen Receptor Modulator.
Wills S, Ravipati A, Venuturumilli P, Kresge C, Folkerd E, Dowsett M, Hayes D, Decker DA Beaumont Hospitals, Royal Oak, MI; Royal Marsden Hospital, London, United Kingdom; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
Introduction: Intravaginal estradiol (E2) has been proposed as a safe alternative to systemic estrogen therapy. We report serum E2 levels in breast cancer survivors using either vaginal E2 ring (Estring®) or beta E2 tablet (Vagifem®) while also taking an aromatase inhibitor (AI) or selective estrogen receptor modulator (SERM). These patients are compared to a group of breast cancer survivors using an AI but not taking a VE. Patients and Methods: Postmenopausal women with estrogen receptor positive breast cancer (n=24) using an AI or SERM and vaginal estrogens (VE) to control atrophic vaginitis (ring inserted every 90 days; n=10 or 1 tablet inserted 2 x per week; n=14) and 24 control survivors using an AI without VE were enrolled after informed consent. Serum samples were drawn from ring patients pre-insertion and 30 and 60 days post insertion, from tablet patients the morning prior to insertion and 12 hours post insertion, and from controls taking an AI >14 d. Serum samples were assayed for E2 concentrations by highly sensitive radio-immunoassay (Cancer Res 1987;47:1957). Statistical analyses were carried out using SAS® System, v. 9.2. Results: Patient data are provided in tables 1 and 2 (control data not shown). Circulating E2 levels pre-insertion in tablet patients were not significantly different than those in control patients (mean difference=4.7 pmol/l SD:3.2; CI: 2.9-4.9, p=0.48). E2 levels pre-insertion in patients using the ring were significantly greater than controls (mean difference=14.2 pmol/l; SD:7.2;CI, 11-19:p=0.0001). In tablet patients, E2 levels at 12 hours post insertion were 76 pmol/l higher than at pre-insertion baseline (SD:97; CI, 14-89, p<0.0001), and E2 levels at 12 weeks post insertion in ring patients were 30 pmol/l higher than at pre-insertion baseline(SD:50; CI: 10-20, p=0.001). Discussion: Our data did not show a significant difference in pre-insertion E2 levels for the tablet compared to controls, but we did observe a significant difference in pre-insertion E2 levels for the ring compared to controls. Importantly, we also observed a significant elevation in E2 levels in most patients using VEs post insertion, regardless of the type of device (tablet or ring). The clinical significance of vaginal E2 absorption is unknown, although elevated E2 levels are diametrically opposite of the desired effect for breast cancer patients taking an AI. Vaginal estrogen in patients receiving an adjuvant AI must be advised with caution.
Treatment for Vaginal Dryness: Testosterone vs Estring
[5038] A Phase II Study of Vaginal Testosterone Cream (TEST) vs. Estring for Vaginal Dryness or Decreased Libido in Women with Early Stage Breast Cancer (BC) Treated with Aromatase Inhibitors (AIs).
Melisko ME, Rugo HS, DeLuca A, Park JW, Moasser M, Munster P, Goldman M University of California San Francisco, San Francisco, CA
Background: Sexual issues including vaginal dryness and decreased libido are common among breast cancer patients. Many interventions are hormonally based. The risk of these treatments is unknown and is of interest, particularly for patients with hormone receptor positive disease. Design: In a randomized open label study, we are evaluating the safety, based on serial measurements of serum estradiol (E) levels, of intravaginal TEST or Estring used for 12 weeks (wks) for relief of vaginal dryness and/or decreased libido in women with early stage BC taking AIs. Planned enrollment is 35 patients (pts) per arm, and accrual will stop if a predetermined number of pts has a sustained elevation in serum E while on study. E is measured by an ultrasensensitive liquid chromatography-tandem mass spectrometry based assay. Eligible pts have not had a menstrual period for 12 months. and have taken an AI for at least one month. Pts who received chemotherapy or who are on ovarian suppression must have a serum E of <10 pg/ml during the screening period. Pts are randomized to Estring 2mg for 12 wks or TEST inserted vaginally at a dose of 0.5 grams daily for 2 wks and then three times a week for 10 wks. Pts undergo a gynecologic exam at baseline and at wk 12 to score vaginal atrophy including measures of rugae, dryness, pallor, petachiae, and mucosal thinning. Serum E levels and a validated sexual quality of life questionnaire are collected at baseline, then at wks 4 and 12. Pts randomized to TEST have serum testosterone drawn at the same time points. Serum E levels are repeated at wk 8 and/or wk 16 if the level is elevated at either wk 4 or wk 12 to > 10 pg/ml or if there is a > 10 pg/ml elevation above their baseline value.
Results: 29 pts have been enrolled; 15 to TEST, 14 to Estring. 20 pts have completed the 12 wk study period. Adverse events are rare and include grade 1 vaginal discharge, odor, or burning, and hair growth. Two pts did not complete the study due to the Estring falling out. One pt discontinued Estring due to vaginal discharge and irritation. One pt using TEST discontinued treatment due to a herpes outbreak. Among the Estring pts, two had an elevation in serum E to >10 pg/ml (14 pg/ml and 70 pg/ml) at wk 4 or at wk 12; but E returned to <10 pg/ml 4 wks later. Among pts using TEST, four had an elevation of serum E to > 10pg/ml at wk 4 or at wk 12; one remained modestly elevated (17 pg/ml) 4 wks later. Vaginal atrophy scores showed improvement in pts receiving both treatments, although the study is not powered to show a difference between the two arms.
Conclusions: Both vaginal TEST and Estring appear to be effective options to treat vaginal dryness in pts with early stage BC on AIs. The number of pts with sustained elevations in serum E levels to date has not reached the pre-defined threshold for stopping the study.
“Deadly” finding in Tamox/SSRI users
[2049] Risk of Death Due to Breast Cancer in Women Treated with Selective Serotonin Reuptake Inhibitor Antidepressants and Tamoxifen. Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, Paszat LF Institute of Clinical Evaluative Sciences, Toronto, ON, Canada; Sunnybrook Health Sciences Centre, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada Background: Tamoxifen is widely prescribed to women with breast cancer, but is a prodrug converted by cytochrome P450 2D6 (CYP 2D6) to its active metabolite endoxifen. Selective serotonin re-uptake inhibitor antidepressants (SSRIs) are commonly co-prescribed with tamoxifen, but inhibit CYP 2D6 to varying degrees and may decrease the effectiveness of tamoxifen. Materials and methods: We conducted a population-based retrospective cohort study of women in Ontario, Canada aged 66 years of age or older who were treated with tamoxifen for breast cancer between 1993 and 2005 and had overlapping SSRI therapy. Following completion of tamoxifen therapy, we modeled the risk of death from breast cancer as a function of the proportion of time on tamoxifen during which each SSRI had been co-prescribed. Results: We identified 24,430 women aged 66 years and older who started tamoxifen therapy during the 13 year study period. Of these, 7489 (30.6%) received at least one antidepressant during tamoxifen therapy. After excluding those treated with no SSRI or with multiple SSRIs, those with poor adherence to tamoxifen therapy, and those with unknown cause of death, the primary analysis included 2430 women. Paroxetine was the most commonly prescribed SSRI (n=630; 25.9%) followed by sertraline (n=541; 22.3%), citalopram (n=467; 19.2%), venlafaxine (n=365; 15.0%) fluoxetine (n=253; 10.4%) and fluvoxamine (n=174; 7.2%). A total of 1074 (44.2%) women died during follow-up and there were 374 (34.8%) breast cancer deaths. After adjustment for age, duration of tamoxifen therapy, and other potential confounders absolute increases of 25%, 50%, and 75% in the percentage of time co-prescribed paroxetine during tamoxifen therapy were associated with 24%, 54% and 91% increases in the risk of death from breast cancer respectively (p<0.05 for each comparison). In contrast, we found no such risk with fluoxetine, sertraline, fluvoxamine or citalopram. We observed a nonsignificant trend toward reduced breast cancer mortality among venlafaxine users, which may reflect the common practice of using venlafaxine for tamoxifen-related hot flashes, a putative predictor of better outcomes in women receiving tamoxifen. We replicated our analyses using death from any cause as the outcome of interest (n=1074). After adjusting for potential confounders, we found that absolute increases of 25%, 50% and 75% in paroxetine exposure during tamoxifen therapy were associated with relative increases of 13%, 28% and 46%, respectively, in the risk of death from any cause. In contrast, we found no such increased risk in all-cause mortality associated with exposure to the other SSRIs in women receiving tamoxifen for breast cancer. Discussion: Paroxetine use during tamoxifen therapy is associated with an increased risk of death due to breast cancer. This supports the hypothesis that paroxetine-mediated CYP 2D6 inhibition can reduce or abolish the beneficial effects of tamoxifen.
Vitamin D helps reduce AI pain
[803] A Double-Blind, Randomized, Placebo-Controlled Trial of High Dose Vitamin D Therapy on Musculoskeletal Pain and Bone Mineral Density in Anastrozole-Treated Breast Cancer Patients with Marginal Vitamin D Status. Rastelli AL, Taylor ME, Villareal R, Jamalabadi-Majidi S, Gao F, Ellis MJ Siteman Cancer Center, Washington University, St. Louis, MO; Washington University, St. Louis, MO Rationale: Musculoskeletal (MS)pain is a known adverse class effect of aromatase inhibitors. Previously we reported high prevalence of Vitamin D deficiency in breast cancer patients complaining of MS pain, and anecdotal improvement of MS pain with weekly supplementation of high dose Vitamin D (HDD) (1). Here we report on a randomized double-blind, placebo-controlled trial of weekly HDD (ergocalciferol 50,000 IU) versus placebo (PBO) in breast cancer patient receiving anastrozole, with new or worsening MS pain since initiation of treatment, and with marginal levels of 25-OH Vitamin D (25OHD). The secondary aim was to determine whether HDD supplementation protects from bone loss. Methods: Inclusion criteria: 1) Postmenopausal women with invasive breast cancer (stage I - IIIB) on Anastrozole for at least 8 weeks; 2) new or worsening MS pain; 3) serum 25OHD level between 10 and 29 ng/ml. Design: 2 strata: 1) if 25OHD levels between 20-29 ng/ml, patients received 8 weeks of HDD then monthly HDD until the end of study (6 months) or PBO; 2) if 25OHD levels between 10-19 ng/ml, patients received 16 weeks HDD followed by monthly HDD until the end of the study or PBO. In addition, all patients received calcium (1000 mg/day) and standard Vitamin D supplementation (400 IU/day). Pain was measured by validated questionnaires (BPI, HAQ, FIQ) at baseline, month 2, month 4 and month 6. Bone Mineral Density was measured at baseline and at 6 months using a Hologic densitometer. Results: Sixty patients were enrolled. Mean age was 61.5 years. HDD and PBO groups did not differ at baseline in pain scores and 25OHD levels. At 2 months the HDD group reported lower scores on pain-related questions on BPI (question #3) at 2 mo, p=0.01 and FIQ (question #15), at 2 mo p=0.02. There was also a trend for better scores for walking and climbing steps on the HAQ [Group x Time Chi-square=3.6; at 2 mo p=0.02; p=0.009 at 4 mo]. Preliminary analysis of bone density data show higher femoral neck values in the HDD group at 6 months [% change 0-6 mo: HDD=0.54±0.71, PBO= -1.43±0.66, p=0.05]. There were no significant toxicities. Conclusions: HDD is well tolerated in this study, improves MS pain in patients receiving anastrozole, and may help functional activity. The effect was limited to the 2 month interval when patients on the active arm were receiving weekly treatment. Improvements decreased at 4 and 6 months once patients switched to monthly supplements. HDD may have also a positive effect on bone health. Limits of this pilot randomized study include the small number of patients, and the difficulty of measuring pain using clinical questionnaires. 1) Taylor ME, Rastelli A, et.al. Incidence of 25-OH vitamin D deficiency in patients with a history of breast cancer who have musculoskeletal symptomatology. San Antonio Breast Cancer Symposium, Poster # 3072, December 2004 Supported by Astra-Zeneca
Zometa Reverses Bone Loss in AI patients post chemotherapy
[2103] Zoledronic Acid for Treatment of Osteopenia and Osteoporosis in Women with Primary Breast Cancer (BC) Undergoing Adjuvant Aromatase Inhibitor (AI) Therapy. Hines SL, Sloan JA, Atherton PJ, Perez EA, Dakhil SR, Johnson DB, Reddy PS, Dalton RJ, Mattar BI, Loprinzi CL Mayo Clinic Florida, Jacksonville, FL; Mayo Clinic Rochester, Rochester, MN; Wichita Community Clinical Oncology, Wichita, KS; Immanuel-St. Joseph Hospital Mayo Health System, Mankato, MN Background: Postmenopausal women with significant osteopenia/osteoporosis are at increased risk of fracture, a risk that is exacerbated by the use of Aromatase Inhibitors (AIs). Bisphosphonates may be used for these patients because there is no known interaction with estrogen and/or progesterone receptors (ER, PR). This study evaluated the concurrent use of zoledronic acid in patients with significant osteopenia or osteoporosis who received initial adjuvant letrozole therapy for primary BC, to determine if further bone mineral density (BMD) loss could be prevented. Methods: Postmenopausal women with Stage I-IIIa, ER and/or PR + BC, no evidence of metastatic disease, and a BMD T-score < -2.0 were treated with daily letrozole 2.5 mg/d, vitamin D 400 international units/d, calcium 500 mg twice daily, and 4 mg I.V. zoledronic acid every 6 months (for 5 years). The BMD was measured at baseline and at one year. Kruskall-Wallis p-value methodology was used as the method of statistical analysis. Since this was a single-arm study, the analysis plan was primarily descriptive. The primary endpoint was the mean change in lumbar spine (LS) BMD at 1 year. Results: 60 patients were enrolled; 46 completed 1 year of treatment. Mean patient age was 67 years, with 44% having taken prior tamoxifen. At 1 year (see figure 1), LS BMD increased 2.66% (p=0.01), femoral neck (FN) BMD increased 4.81% (p=0.01), and any measured endpoint (within the LS or FN) increased 4.55% (p=0.0052). 7% of patients experienced a fracture vs.13% with a pre-existing history of fracture before enrollment. No patients had disease recurrence during year 1. Toxicity was minimal with arthralgia as the most common complaint. There were no reports of osteonecrosis of the jaw. Conclusion: Zoledronic acid prevents additional bone loss in postmenopausal women with significant osteopenia or osteoporosis initiating letrozole. Treatment with zoledronic acid was associated with an improvement in BMD.
Scalp Hypothermia can Prevent Hair Loss in Non-Anthracycline Treated Patients
[5040] Scalp Hypothermia Minimizes Alopecia in Breast Cancer Patients Receiving Non-Anthracycline Adjuvant Chemotherapy.
Wills S, Ravipati A, Nguyen M, Dana Z, Jaiyesimi I, Margolis J, Decker D William Beaumont Hospital, Royal Oak, MI
Background: Chemotherapy induced alopecia (CIA) is considered the most distressing side effect of chemotherapy for breast cancer patients. Scalp hypothermia offers hope to minimize chemotherapy induced alopecia (CIA) for breast cancer patients. We present data from a pilot study of scalp hypothermia with the Penguin Cold Cap System™ in patients receiving a combination chemotherapy regimen. Patients and Methods: Stage I-IIIC breast cancer patients, receiving adjuvant chemotherapy regimens with or without (A) were consented. Standard dose regimens included doxorubicin-cyclophosphamide (AC) x 4 cycles, dose dense, doxorubicin-cyclophosphamide followed by taxol (AC-T) x 8 cycles, taxotere-doxorubicin-cyclophosphamide (TAC) x 6 cycles, taxotere-cyclophosphamide (TC) x 4 cycles and taxotere-carboplatnium-trastuzumab (TCH) x 6 cycles. Photos were taken before and with each cycle and 3 weeks post chemotherapy, Dean's alopecia scale was used for grading. Caps were cooled to 8oC. Caps 1-2 were 20 minutes each prior to infusion, following caps were changed q 30 minutes throughout chemotherapy and for 3 hours post-chemotherapy. Results: See tables 1 and 2 for patient data. We enrolled 34 patients (22 (A) containing; 12 non (A) containing) after informed consent. Of patients withdrawn, 1 patient (AC-T) had metastatic disease at the time of registration and did not start scalp hypothermia,1 patient (TC) had scalp discoloration; 2 patients (AC and TAC) withdrew due to discomfort of cooling; 1 patient (TC) withdrew prior to start of therapy due to fear of discomfort and 1 patient (AC) was withdrawn for coloring hair at time of treatment. The mean percent of CIA in the (A) containing group was 52% (SD: 17 CI: 40-70) and the mean percent CIA in non (A) containing group was 25% (SD: 36 CI: 5-100). A comparison of the means yielded a p-value of 0.0003 in favor of non (A) containing regimens. Of the 12 patients in the non (A) containing regimen 83% (3 TCH, 7 TC) did not require a prostheses and of the patients receiving an (A) containing regimen 47% (8 AC) did not require a prostheses. For those patients who completed scalp hypothermia through chemotherapy, the median CIA for TC and TCH combined was 10% hair loss (5,25) and for AC, AC-T and TAC combined was 50% hair loss (45,70). Discussion: All patients who received TAC or AC-T had grade 4 CIA and needed a hair prostheses. Most AC patients preserved some of their hair. Hair thinning was even and not patchy in this group and most had no need for prostheses. Patients in the TC or TCH group, who were able to complete the scalp hypothermia therapy, retained 90% or better, of their hair and there was no need for prostheses in these groups. We found the scalp hypothermia technique used here reduces hair loss in AC patients and offers the possibility of CIA prevention for women with breast cancer receiving TC or TCH.
Treatment and Prevention of Osteonecrosis of the Jaw
[5046] Medical Ozone (O3) Oil or Gas Applications Heal Osteonecrosis of the Jaw (ONJ) in Patients Treated with Bisphosphonates (BPs). Preliminary Results of a Single Arm Study.
Ripamonti C, Maniezzo M, Ghiringhelli R, Cislaghi E, Mariani L National Cancer Institute of Milan, Milan, Milan, Italy; Sanipan S.r.l, Clivio, Varese, Italy
Treatment of bone metastasis with BP is aimed at preventing skeletal related events (SREs) and rarely leads to ONJ (<1%) (Hoff, JBMR. 2008). Preventive dental care is a simple and effective way to reduce the risk reduction of ONJ in 75% of the cases (Ripamonti, Ann Oncol. 2009). To date, there are still no standardized therapy for the treatment of ONJ. We report the effect of localized of O3 oil or gas application in cancer patients (12 breast cancer, 4 prostate cancer, 2 lung cancer, 1 NHL, 3 multiple myeloma) with ONJ observed in our institution. Patients had previously received nitrogene-BPs treatment in the absence of odontoiatric preventive measures. All the patients were in had stable disease without progression; 10 of them had ONJ lesions ≤ to 2.5 cm.
O3 oil suspension applications on ONJ lesions ≤ 2.5 cm was carried out with localized applications directly on the lesions; patients with larger lesions (≥ 2.5 cm) were treated with the ozone gas locally applied. All the patients received treatment of O3 oil every third day and all of them were treated with antibiotic therapy (azithromycin, 500 mg/day) 10 days prior the initiation of the treatment with O3 oil. The statistical analysis is based on a Simon two-stage design, the second stage is on-going. In this preliminary analysis we focus on 10 patients treated with O3 oil with a medium follow up of 8 months, and 12 patients on medical gas ozone.
73% of the patients (n=16) showed complete response in terms of radiological lesion disappearance with complete reconstruction of oral tissue. Among them, fourteen patients developed spontaneous sequestrum with expulsion of the necrotic bone whereas in 2 patients with large extension of bone involvement surgical intervention was necessary.
Seventy percent of the patients treated with O3 oil experienced a complete response after 4 applications whereas patients treated with gas needed 4 to 16 applications (depending on the severity of the lesion). No patients presented adverse events related to the use of ozone treatments. Six patients are still on treatment and are improving as well.
According to these results few application of O3 oil suspension in patients with smaller lesions and gas medical ozone for wider lesions following antibiotic therapy can rapidly lead to complete healing of ONJ. Further cases and complete follow-up data are required. These data indicate that ONJ is a manageable condition which can be not only prevented by means previously dental examination but also healed with medical ozone applications.
AIs Can Prevent Lung Cancer
[35] Reduced Lung Cancer Mortality Risk among Breast Cancer Patients Treated with Anti-Estrogens.
Rapiti E, Verkooijen HM, Fioretta G, Schubert H, Vinh-Hung V, Benhamou S, Vlastos G, Bouchardy C University of Geneva, Geneva, Switzerland; University of Singapore, Singapore, Singapore; University Hospital, Brussel, Belgium; University Hospitals, Geneva, Switzerland; Inserm, Paris, France
Background: The Women Health Initiative study recently reported that women on hormone replacement therapy (HRT) were at increased risk of dying from lung cancer. If exposure to estrogens can worsen lung cancer outcome, we hypothesized that anti-estrogens may, on the contrary, improve its prognosis. We compared lung cancer incidence and mortality among breast cancer patients with and without anti-estrogen therapy.
Methods: All 6715 patients recorded with a breast cancer in the population-based Geneva Cancer registry in the period 1980-2003 were included in the study. Forty-six percent of these women (3066) received anti-estrogen therapy (tamoxifen in large majority). Age, sex and year-specific population data were used to calculate standardised incidence ratios (SIRs) and standardised mortality ratios (SMRs), to compare the study population to the general female population of Geneva canton. For each woman we computed person-years at risk from the date of diagnosis of breast cancer to the date of diagnosis of invasive lung cancer cancer, date of death, date lost to follow-up, or end of the study period (December 31, 2007).
Results: The cohort yielded a total of 57,100 person-years.
During the study period we observed a total of 40 cases of metachronous lung cancers (diagnosed at least six months after the breast cancer). Compared with the general population, the risk of developing a lung cancer among women who received anti-estrogens was 0.63 (95% Confidence Intervals [CI]: 0.33-1.10) and among women without anti-estrogens was 1.12 (95% CI: 0.74-1.62). Lung cancer mortality rate was 31.44/100,000. The mortality rate were 9.23/100,000 for women with anti-estrogens and 44.97/100,000 for women without anti-estrogens.
Compared to the general population the SMR for lung cancer was 0.13 (95% CI: 0.02-0.47) among women who took anti-estrogens (p<0.001), and 0.76 (95% CI: 0.43-1.23) among women who did not receive anti-estrogens.
Discussion: Women who received anti-estrogens as breast cancer treatment have a significantly decreased risk of dying from lung cancer. This result further supports the role of estrogens in lung cancer prognosis and suggests that exposure to anti-estrogens may offer some protection against tumor mortality.
Weight, Blood Pressure and Lipids and Survival
[3047] Metabolic Profile (Blood Pressure, Lipids and Body Mass Index) in Relation to Breast Cancer Mortality.
Emaus A, Veierød MB, Tretli S, Finstad SE, Selmer R, Furberg A-S, Bernstein L, Schlichting E, Thune I Oslo University Hospital, Ullevål, Oslo, Norway; Institute of Basic Medical Sciences, Oslo, Norway; Institute of Population-Based Cancer Research, Oslo, Norway; Norwegian Institute of Public Health, Oslo, Norway; Institute of Community Medicine, University of Tromsø, Tromsø, Norway; Division of Cancer Etiology, Duarte, CA
Background: Metabolic profile (body mass, blood pressure, lipids) may affect biological mechanisms of importance for breast cancer. In the present study we have studied whether these factors are related to breast cancer mortality.
Material and Methods: Within the Norwegian Counties Study, a population-based study (1974-2005), we identified 1364 female invasive breast cancer cases.
Results: The 1364 cases had a mean age at diagnosis 57.5 years (range 27.1-79.4 years), mean body mass index (BMI) was 24.0 kg/m2, mean systolic blood pressure was 128.1 mmHg, mean diastolic blood pressure 78.6 mmHg, mean serum cholesterol was 6.17 mmol/L and mean HDL-cholesterol was 1.45 mmol/L. A total of 429 cases died during a mean follow-up of 8.2 years. Those with a BMI ≥30 kg/m2 had a 1.45 (CI, 1.07 to 1.95) higher risk of dying during the follow-up than women with a BMI of 18.5–25 kg/m2. Women in the highest tertile of blood pressure had a 43% increase in mortality compared to women in the lowest tertile of blood pressure (HR=1.43, 95% CI, 1.10 to 1.85). Additionally, women in the highest tertile of total cholesterol had a 29% increase in mortality compared to women in the lowest tertile (HR=1.29, 95% CI, 1.01 to 1.65).
Conclusion: Our study supports a relationship between total mortality among breast cancer patients and metabolic profile.
Testosterone to Treat AI Joint Pain
[804] Testosterone Undecanoate Treatment Reduces Joint Morbidities Induced by Anastrozole Therapy in Postmenopausal Women with Breast Cancer: Results of a Double-Blind, Randomized Phase II Trial.
Birrell SN, Tilley WD Chavah Pty Ltd, Adelaide, South Australia, Australia; Hanson Institute and School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
Background: Approximately 50% of women taking 3rd generation aromatase inhibitors (AI) for adjuvant breast cancer therapy develop arthralgia, tenosynovitis or arthritis. In many women, the morbidity is significant and affects therapy compliance. The pathology of AI-induced joint morbidity is poorly understood, but clinical features in severe cases mimic rheumatoid arthritis. Afflicted women are treated with anti-inflammatory medication, but this does not address the etiology, which appears to involve steroid hormone imbalance. Testosterone can be metabolised to estrogen or the more potent androgen, 5alpha-dihydrotestosterone (DHT). Androgen levels decrease with age and this may be exacerbated by chemotherapy and, paradoxically, aromatase inhibition. We hypothesise that AI-associated joint morbidities are the result of testosterone deficiency and that testosterone treatment during AI therapy will be beneficial. Testosterone replacement had been contraindicated in women with breast cancer until the advent of powerful 3rd generation aromatase inhibitors that are highly efficacious in blocking conversion of testosterone to estrogen, thus allowing the examination of combinations of drugs such as anastrozole and testosterone.
Materials and Methods: 90 women taking Arimidex® 1mg daily and registering a visual analogue scale (VAS) pain or stiffness score of ≥ 40mm on a 100mm scale, were randomized into 3 equal arms: placebo, 40 mg or 80 mg testosterone undecanoate daily, with follow-up at 1 and 3 months. The primary efficacy endpoint was reduction in pain at 3 months and the primary safety endpoints were signs of androgen excess with secondary safety endpoints being serum hormone levels, serum lipids and bone absorption markers.
Results: The VAS scores at 3 months fell for all groups, with a marked placebo effect of 35% compared with 43% and 70% for the 40 and 80mg treatment arms (p=0.06 and p=0.04, respectively). No significant androgenic side-effects (hirsutism, alopecia and acne) were observed and serum lipids remained unaltered. Serum total testosterone and free-testosterone levels stabilized at 3 months in a dose-dependent fashion into a physiological range. There was no elevation in serum estradiol in either treatment arm and the serum sex hormone binding globulin level fell significantly in the 80mg treatment group (p=0.03). There was no significant change in bone absorption markers in any of the patient groups.
Discussion: This study has demonstrated for the first time that testosterone replacement may be a viable option in the management of AI-induced arthralgia, tenosynovitis and arthritis with good tolerability and safety, without adversely reducing aromatase inhibitor efficacy (as indicated by serum estradiol levels).
This study was supported AstraZeneca (UK).
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