Treatment of Triple Negative Disease
Take Your Vitamin D- Especially if you are Triple Negative
We have been encouraging No Surrender readers to take their Vitamin D since our inception. Now, a study we have been following, has yielded great results- especially if you have triple negative breast cancer. We recommend Vitamin D supplementation no matter what your receptors are and suggest that women who do not have breast cancer also supplement to keep their D levels in good range.
Vitamin D Holds Promise in Battling a Deadly Breast Cancer
Wed, 2013-01-23 11:34
In research published in the Jan. 21 issue of The Journal of Cell Biology, a team led by Susana Gonzalo, PhD, assistant professor of biochemistry and molecular biology at Saint Louis University, has discovered a molecular pathway that contributes to triple-negative breast cancer, an often deadly and treatment resistant form of cancer that tends to strike younger women. In addition, Gonzalo and her team identified vitamin D and some protease inhibitors as possible new therapies and discovered a set of three biomarkers that can help to identify patients who could benefit from the treatment.
In the recent breakthrough, which was funded in part by a $500,000 Department of Defense grant, Gonzalo’s lab identified one pathway that is activated in breast cancers with the poorest prognosis, such as those classified as triple-negative. These cancers often strike younger women and are harder to treat than any other type of breast cancer. Women who are born with BRCA1 gene mutations are at increased risk for developing breast and ovarian cancers within their lifetime, and the tumors that arise are frequently the triple-negative type. Although chemotherapy is the most effective treatment for triple-negative breast cancer, it has profound secondary effects. Understanding the biology of triple-negative breast cancers will help to develop less toxic therapeutic strategies.
Experiments performed in Gonzalo's laboratory, in collaboration with the laboratories of Xavier Matias-Guiu and Adriana Duso (IRBLleida, Spain), showed that activation of this novel pathway not only allows tumor cells to grow unchecked, but also explains the reduced sensitivity of these types of tumors to current therapeutic strategies. Importantly, vitamin D plays a role in turning off this pathway, providing a safe and cost-effective strategy to fight these types of tumors.
For molecular biologists like Gonzalo who look for answers below the cellular level to discover why some people develop cancer, the search often involves tracing a chain of events to try to understand cause and effect of the behavior between several genes and the proteins which they express. In order to understand these complex pathways, researchers often turn levels of proteins on or off by expressing one gene or suppressing another. Part of a researcher’s challenge is determining what the function of each component of a pathway is.
The cell employs a complex mechanism to protect genetic information and ensure that damaged DNA is not passed on to daughter cells. Cells have built in checkpoints and fail safes to ensure the accuracy of their DNA code and are able to slow or stop their own proliferation if the information is compromised. Loss of these checkpoints and the accumulation of damaged DNA often leads to cancer.
BRCA1 is a well-established tumor suppressor gene. Women who carry mutations in this gene have a high risk of developing breast and ovarian cancer. Tumors that arise often lack expression of three receptors: estrogen, progesterone and HER2 (thus, “triple-negative”), and do not respond to hormone therapy.
BRCA1 is important because it is involved in repairing DNA double-strand breaks, a kind of DNA damage that is especially dangerous for the integrity of our genome. BRCA1 also is involved in cell-cycle checkpoints after damage, which are control mechanisms during cell proliferation that make sure the DNA information has been accurately replicated and transferred to the daughter cells. Thus, BRCA1 is considered a safeguard of the genome.
Loss of BRCA1 is bad news for the information contained in a cell’s genetic blueprint. It results in genomic instability characterized by unrepaired DNA breaks and chromosomal aberrations that compromise cell viability. How BRCA1-mutated cells are able to form tumors has been a long-standing question. Investigators recently showed that loss of another DNA repair factor, 53BP1, allows proliferation and survival of BRCA1-deficient cells. In addition, decreased levels of 53BP1 were observed in triple-negative breast cancers, and correlated with resistance to drugs at the forefront of cancer treatment, such as PARP inhibitors.
Gonzalo’s team has found a pathway responsible for the loss of 53BP1 in breast cancers with poor prognosis, specifically BRCA1 mutated and triple-negative. It turns out that loss of BRCA1 increases the expression of a protease, known as cathepsin L (CTSL), which causes the degradation of 53BP1. Cells that have lost both BRCA1 and 53BP1 have the ability to repair DNA, maintain the integrity of the genome, and proliferate. Thus, the protease helps cells with faulty BRCA1 to survive.
If lowering the levels of 53BP1 allows BRCA1 deficient cells to thrive and do their worst, increasing the levels of the protein offers a promising strategy for treatment of breast tumors.
So, how to do this? In previous research, Gonzalo’s team showed that vitamin D inhibits CTSL-mediated degradation of 53BP1 in non-tumor cells, as efficiently as specific CTSL inhibitors. This time, they found that treatment of BRCA1-deficient tumor cells with vitamin D restores high levels of 53BP1, which results in increased genomic instability and reduced proliferation.
Importantly, their evidence suggests that vitamin D treatment might restore the sensitivity to PARP inhibitors in patients who become resistant. Thus, a combination of vitamin D and PARP inhibitors could represent a novel therapeutic strategy for breast cancers with poor prognosis.
So, with this chain of events, Gonzalo and colleagues demonstrated a pathway by which triple-negative breast cancers proliferate: BRCA1-deficient cells activate CTSL which minimizes levels of 53BP1 to overcome genomic instability and growth arrest.
In a final exceptionally useful discovery, Gonzalo and collaborators found that high levels of nuclear CTSL and low levels of 53BP1 and nuclear vitamin D receptor (VDR) are a clear marker that identifies certain triple-negative breast cancer patients, biomarkers that offer the potential to customize future breast cancer therapies. In particular, this triple-biomarker signature will allow the identification of patients in whom the pathway is on and who might benefit the most from vitamin D treatment.
From OncologyNurseAdvisor
January 14, 2013
Newfound marker for aggressive breast cancer may also be a treatment target
The findings of a recent study strongly implicate the ribonucleic acid (RNA) molecule miR-181a as a predictive biomarker for breast cancer metastasis and patient survival, which in turn makes the molecule a potential therapeutic target in metastatic breast cancer.
As explained in a statement issued by Case Western Reserve University in Cleveland, Ohio, miR-181a had never before been tied to breast cancer metastasis. However, William P. Schiemann, PhD, of the Case Comprehensive Cancer Center, and colleagues found elevated levels of the molecule in late-stage breast cancer tissues.
The investigators described in The Journal of Clinical Investigation (2013;123[1]:150-163) their discovery that miR-181a expression was essential in driving metastasis and enhancing the lethality of late-stage mammary tumors in mice. In addition, miR-181a expression was dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and was highly predictive for decreased overall survival in humans with breast cancer.
An inhibitor of miR-181a tested in the mice prevented metastasis and extended survival.
“Overall, these findings reinforce our belief that the discovery of miR-181a will become a strong predictive biomarker for breast cancer metastasis, and that the high expression of miR-181a in tumor tissues will pave the way for the development of targeted therapies, better prognosis, and increased patient survival,” commented Schiemann in the Case Western statement.
Septemner 6, 2012
UT MD Anderson Cancer Center Launches Unprecedented Moon Shots Program
Effort sets new bar for eradicating cancer; Goal to significantly increase patient survival during the next decade
HOUSTON — The University of Texas MD Anderson Cancer Center announces the launch of the Moon Shots Program, an unprecedented effort to dramatically accelerate the pace of converting scientific discoveries into clinical advances that reduce cancer deaths.
Even as the number of cancer survivors in the US is expected to reach an estimated 11.3 million by 2015, according to the American Cancer Society, cancer remains one of the most destructive and vexing diseases. An estimated 100 million people worldwide are expected to lose their lives to cancer in this decade alone. The disease’s devastation to humanity now exceeds that of cardiovascular disease, tuberculosis, HIV and malaria – combined.
The Moon Shots Program is built upon a “disruptive paradigm” that brings together the best attributes of both academia and industry by creating cross-functional professional teams working in a goal-oriented, milestone-driven manner to convert knowledge into tests, devices, drugs and policies that can benefit patients as quickly as possible.
The Moon Shots Program takes its inspiration from President John Kennedy’s famous 1962 speech, made 50 years ago this month at Rice University, just a mile from the main MD Anderson campus. “We choose to go to the moon in this decade ... because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win,” Kennedy said.
“Generations later, the Moon Shots Program signals our confidence that the path to curing cancer is in clearer sight than at any other time in history,” said Ronald A. DePinho, M.D., MD Anderson’s president. “Humanity urgently needs bold action to defeat cancer. I believe that we have many of the tools we need to pick the fight of the 21st century. Let’s focus our energies on approaching cancer comprehensively and systematically, with the precision of an engineer, always asking ... ‘What can we do to directly impact patients?’”
The inaugural moon shots
The program, initially targeting eight cancers, will bring together sizable multidisciplinary groups of MD Anderson researchers and clinicians to mount comprehensive attacks on:
Six moon shot teams, representing these eight cancers, were selected based on rigorous criteria that assess not only the current state of scientific knowledge of the disease across the entire cancer care continuum from prevention to survivorship, but also the strength and breadth of the assembled teams and the potential for near-term measurable success in terms of cancer mortality.
Each moon shot will receive an infusion of funds and other resources needed to work on ambitious and innovative projects prioritized for patient impact, ranging from basic and translational research to biomarker-driven novel clinical trials, to behavioral interventions and public policy initiatives.
The platforms make the program unique
The institution-wide, high quality scientific and technical platforms will provide key infrastructure for the success of the Moon Shots Program. In the past, each investigator or group of investigators has developed their own infrastructure to support their research programs. Frequently they were under-funded and lacked the high level management and leadership required to ensure that they were of the highest caliber and in particular that they were able to adapt to the rapidly changing scientific and technological environment. The moon shot platforms will be designed and resourced to provide expertise that will support the efforts of all of moon shots teams. The platforms will provide a critical component to the success of each moon shot and of the overall Moon Shots Program. In particular, they will leverage the investment across the moon shots.
These platforms include:
Adaptive Learning in Genomic Medicine: A work flow that enables clinicians and researchers to integrate real-time patient clinical information and research genomic data, allowing understanding of the cancer genome and ultimately improving outcome.
Big Data: The capture, storage and processing of huge amounts of information, much of it coming from Next Generation Sequencing machines (genome sequencing).
Cancer Control and Prevention: Community-based efforts in cancer prevention, screening, and early detection and survivorship to educate and achieve a measureable reduction in the cancer burden. Interventions in the areas of public policy, public education, professional education and evidence-based service delivery can make a measurable and lasting difference in our community, especially among those most vulnerable - the underserved.
Center for Co-Clinical Trials: Uses mouse or cell models of human cancers to test new drugs or drug combinations and discover the subset of patients most likely to respond to the therapy.
Clinical Genomics: An infrastructure designed to bank and process tumor specimens for clinical tests that can guide medical decisions.
Diagnostics Development: The development of diagnostic tests for use in the clinic to guide targeted therapy.
Early Detection: Using imaging and proteomic technologies to discover markers that can identify patients with early-staged cancers.
Institute for Applied Cancer Science: Developing effective targeted cancer drugs.
Institute for Personalized Cancer Therapy: An extensive infrastructure that analyzes genomic abnormalities in patient tumors to direct them to the best treatments and clinical trials.
Massive Data Analytics: A computer infrastructure that develops or uses computational algorithms to analyze large-scale patient and public data.
Patient Omics: Centralizing collection of patient biospecimens (tumor samples, blood, etc.) to profile genes and proteins (genomics, proteomics) and identify mutations that can guide personalized treatment decisions and predict therapy-related toxicity to improve overall patient outcomes.
Translational Research Continuum: A framework to facilitate efficient transition of a candidate drug from preclinical studies to early stages of human clinical trial testing so effective drugs can be developed in a shorter time and clinical trials can be quicker and cheaper with higher success rates.
MD Anderson’s “Giant leap for mankind”
A year ago, when DePinho was named MD Anderson’s fourth president, he proposed the notion of a moon shot moment. “How can we envision what’s possible to reduce cancer mortality if we think boldly, adopt a more goal-oriented mentality, ignore the usual strictures on resources that encumber academic research and use the breakthrough technology available today?” he asked. Response from the faculty and staff took the form of initial moon shot proposals that targeted several major cancer types and involved large, integrated MD Anderson teams, sometimes numbering in the hundreds.
Frank McCormick, Ph.D., director of the University of California, San Francisco Cancer Center and president of the American Association for Cancer Research, led the review panel of 25 internal and external experts that narrowed the field to the inaugural six moon shots.
“Nothing on the magnitude of the Moon Shots Program has been attempted by a single academic medical institution,” McCormick said. “Moon shots take MD Anderson’s deep bench of multidisciplinary research and patient care resources and offer a collective vision on moving cancer research forward.”
McCormick added, “The process of bringing this amount of horsepower together in such a focused manner is not normally seen in academic medicine and is valuable in and of itself.”
“The Moon Shots Program holds the potential for a new approach to research that eventually can be applied to all cancers and even to other chronic diseases,” DePinho said. “History has taught us that if we put our minds to a task, the human spirit will prevail. We must do this – humanity is depending on all of us.”
For more information, including backgrounders on the inaugural moon shots, please visit www.cancermoonshots.org
February, 2011
STATEMENT ON ACCESS TO THE INVESTIGATIONAL AGENT INIPARIB
Many patients and advocates within the breast cancer community have been following Sanofi’s research on the investigational agent iniparib for the last several years, in the hopes that it might eventually provide a new treatment option for the patients battling metastatic triple negative breast cancer (mTNBC). However, Sanofi recently reported in February 2011, that the
Phase III study of iniparib in combination with gemcitabine and carboplatin, in patients with mTNBC, did not demonstrate an improvement in either progression‐ free survival or overall survival when compared to gemcitabine and carboplatin alone.
As such, the data from this Phase III study do not support an application for approval by the U.S. Food & Drug Administration (FDA). After extensive discussions with the FDA and external breast cancer experts – including several patient advocacy organizations – Sanofi has decided that it is
necessary to initiate new clinical studies of iniparib, in an effort to better understand how the agent works and to identify potential dosing and patient populations.
In the light of the Phase III results and the need to further investigate iniparib, Sanofi and BiPar Sciences have decided to close the current Expanded Access Program (EAP) for all new patient enrollment effective as of August 15, 2011.
In addition, Sanofi and BiPar Sciences recommend that patients currently receiving iniparib (BSI‐201) as part of the EAP discontinue treatment under this program. However, physicians may consider continuing iniparib in combination with gemcitabine and carboplatin, based on the assessment of individual patients. If the decision is made to continue iniparib, the patient needs to be re‐consented.
All patients screened and deemed eligible for the EAP will be allowed to enter into the program until August 15, 2011. Since all eligible patients will be selected during this time, the random selection process administered by the National Organization for Rare Disorders (NORD)
has been discontinued. Enrollment criteria will still be confirmed for patient entry. As before, the patient’s physician will receive email notification when it is acceptable for them to proceed with treatment.
At Sanofi and Bipar Sciences, we feel that closing this EAP – while difficult – is the most responsible course of action, since the clinical benefit of iniparib has not been demonstrated. Additionally, we do not want the iniparib EAP to inadvertently prevent mTNBC patients from accessing other treatment options or participating in clinical trials of other investigational agents.
Patients who are interested in finding out more about clinical trials are encouraged to visit http://www.clinicaltrials.gov.
Sanofi remains committed to advancing the field of breast cancer research by continuing to study iniparib. To this end, Sanofi will be initiating the new iniparib clinical research program in the breast cancer setting in the next few weeks.
Patient & Patient Advocate Q&A
1. If I participated in an iniparib clinical trial and still receive it, will I be able to continue receiving iniparib from the company?
If you are receiving iniparib as a result of your participation in a metastatic triple negative breast cancer (mTNBC) clinical trial and your physician feels that it is appropriate for you to continue receiving iniparib, we do not anticipate any disruption in your access to iniparib, regardless of
whether you are receiving it in the 1st, 2nd, or 3rd line setting.
2. If I am a mTNBC patient currently enrolled in the Expanded Access Program (EAP), will I continue to receive Iniparib?
Yes, if you are already enrolled in the EAP you will continue to receive iniparib through the EAP, until your physician feels it is no longer appropriate. All patients continuing to receive iniparib through the EAP must sign a new consent form, however.
3. If I am a mTNBC patient waiting to be enrolled in the EAP, can I still get in?
Yes, if you are a 2nd, 3rd, or 4th line patient, you will be able to enroll in the EAP until August 15, 2011. Based on the analysis of the Phase III data, we are no longer accepting new 1st line patients into the EAP, because the trial did not demonstrate that iniparib provided a benefit for patients taking iniparib.
After August 15, 2011 , Sanofi will no longer be enrolling any new patients in the program, regardless of line of therapy, due to the negative Phase III study results.
All patients screened and deemed eligible for the EAP will be allowed to enter into the program until August 15, 2011. Since all eligible patients will be selected during this time, the random selection process administered by the National Organization for Rare Disorders (NORD)
has been discontinued. Enrollment criteria will still be confirmed for patient entry. As before, the patient’s physician will receive email notification when it is acceptable for them to proceed with treatment.
Sanofi remains committed to advancing the field of breast cancer research by continuing to study iniparib.
4. What is the timing for the discontinuation of the current EAP program and the initiation of the new clinical trial program?
The EAP will no longer be open for patient enrollment after August 15, 2011. While we are still finalizing the protocol for the new Phase 1B clinical trial of iniparib, we anticipate that it will begin enrolling patients in within the next few weeks. For more information on this study or other clinical trials, please visit www.clinicaltrials.gov.
5. Will the iniparib EAP program continue to enroll patients after the initiation of the new clinical trial program?
No. Providing access to an investigational agent through an EAP can make it very difficult – if not impossible – to simultaneously enroll a clinical trial that is designed to evaluate the same investigational agent.
Additionally, in light of the need to make significant changes to iniparib’s clinical development program, the company does not feel it is appropriate to continue the Expanded Access Program (EAP) when so many important questions about iniparib remain unanswered. Therefore, Sanofi
will be closing the EAP to new patient enrollment after August 15, 2011.
Patients currently enrolled in the EAP will be permitted to remain in the program until their disease progresses or their physicians feel they are no longer receiving benefit from iniparib, as long as they sign a new consent form.
Natural Weapon Against Triple Negative Breast Cancer
Something so simple.... nature healing nature.... Will this be the answer like mold was to penicillin?
Oncolytic Virus Kills Tumor in Triple-Negative Breast Cancer
Caroline Helwick, Medscape
October 25, 2011 (San Francisco, California) — Laboratory studies conducted at the Memorial Sloan-Kettering Cancer Center in New York City suggest that triple-negative breast cancer (TNBC) might respond to treatment with an oncolytic agent.
The findings were reported here at the American College of Surgeons 97th Annual Clinical Congress.
"We found that [the mutant herpes virus] NV1066 is an effective oncolytic agent against triple- negative breast cancer in vitro and in vivo," said Sepideh Gholami, MD, a research fellow in the laboratory of Yuman Fong, MD, which is considered to be at the forefront in oncolytic viral therapy
research.
"Oncolytic viruses are attractive therapeutic agents that destroy tumor cells without the accompanying destruction of normal cells," she said. The mitogen-activated protein kinase (MAPK)signaling pathway is known to be important in TNBC, and activated (phosphorylated) MAPK signaling has been shown to mediate efficient replication of NV1066 through the deletion of the delta gamma(1)34.5 gene.
In other words, she said, TNBC cells have high levels of phosphorylated MAPK, a protein that promotes tumor growth and contributes to resistance to current therapies. The herpes virus specifically targets cells that overexpress this protein, which is the rationale for this approach. The study aimed to determine whether NV1066 could kill TNBC cells effectively. The researchers also examined the functional effects of NV1066 on the MAPK signal transduction pathway during viral infection.
Dr. Gholami and colleagues infected 5 different TNBC cell lines with the NV1066 herpes simplex virus. After treatment with the virus, the most sensitive cell lines demonstrated a 90% cell kill rate within 1 week; the less sensitive lines demonstrated a 70% cell kill rate.
In addition, sensitive cell lines expressed higher baseline levels of phosphorylated MAPK than resistant cell lines, and viral infection caused the downregulation of phosphorylated MAPK by 48 hours, she reported.
"TNBC cells support efficient viral replication, with over 1 million copy numbers observed, which is more than a 1000-fold increase," she said.
"Since baseline phosphorylated MAPK levels positively correlated with sensitivity to NV1066, they might therefore be used as a clinical marker for selecting patients for viral therapy," she suggested.
Tumor Regression Almost Complete
The researchers created flank tumors and injected them with NV1066 or a control compound. Within 5 days, tumor volume significantly decreased in the experimental group; within 3 weeks, they observed "near-complete tumor regression," Dr. Gholami reported.
....keep reading for more good news below!
NEW Targeted Drug Seeks and Destroys TNBC...
This could be big. Breast cancer is not one disease as we all know. Triple Negative Breast Cancer has been on the back burner in terms of new therapies, until now. PARP treatment is changing the future of metastatic TNBC patients. Now, a new, targeted therapy has identified a sub-type of TNBC tumors...
New Subtype of Breast Cancer Responds to Targeted Drug
ScienceDaily (Mar. 2, 2010) — A newly identified cancer biomarker could define a new subtype of breast cancer as well as offer a potential way to treat it, say researchers at Washington University School of Medicine in St. Louis.
Their findings will be published in the March 1 online early edition issue of the Proceedings of the National Academy of Sciences.
The research could further refine what recent breast cancer research has concluded: that breast cancer is not one disease, but many. So far, research has firmly established that at least five subtypes of breast cancer exist, each having distinct biological features, clinical outcomes and responses to traditional therapies.
The biomarker identified by the Washington University researchers is found frequently in breast cancers and especially in those that have poorer outcomes. It stems from overactivation of a gene called LRP6 (low-density lipoprotein receptor-related protein 6), which stimulates an important cell-growth signaling pathway. LRP6 can be inhibited by a protein discovered in the same laboratory, which could become an effective drug against the breast cancer type, the researchers say.
"We found increased expression of the LRP6 gene in about a quarter of breast cancer specimens we examined, and we think LRP6 overexpression could be a marker for a new class of breast cancer," says Guojun Bu, Ph.D., professor of pediatrics and of cell biology and physiology. "In addition, we found that this biomarker is often associated with breast cancers that are either harder to treat or more likely to recur. We already have an agent that seems to be effective against LRP6-overexpressing tumors, which could someday become a therapy for tumors that right now have few treatment options."
The research was conducted primarily by Chia-Chen Liu, a graduate student in the Bu lab, who is a fellow in the Cancer Biology Pathway Program at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.
The researchers' analysis of human breast cancer tissue samples found significant increases in LRP6 levels in 20 percent to 36 percent of the tumors. LRP6 was increased more frequently in ER (estrogen receptor)-negative or HER2 (human epidermal growth factor receptor 2)-negative samples. LRP6 was also increased more frequently in so-called triple-negative breast tumor samples, which test negative for ER, HER2 and PR (progesterone receptor).
In general, patients who have triple-negative breast cancers have an increased risk of disease recurrence after initial treatment and a poorer prognosis. Furthermore, although ER-positive and HER2-positive tumors can be targeted with specific therapies, ER-negative and HER2-negative tumors cannot. So it appears that LRP6 overexpression is often associated with tumors that are currently difficult to treat, says Bu.
Research in the lab had earlier discovered a protein that binds to and inhibits LRP6. This study showed that the protein, called Mesd (mesoderm development), was able to slow the growth of breast cancer cells in the laboratory and to inhibit mammary tumor growth in laboratory mice.
Importantly, mice treated with Mesd did not experience any of the known side effects, such as bone lesions, skin disorders or intestinal malfunctions, associated with inhibition of this growth pathway.
"Our work introduces Mesd as a promising antitumor agent that might be further developed for breast cancer therapy," Bu says. "It would be analogous to such successful breast cancer therapies as Herceptin (trastuzumab), which specifically targets HER2-positive breast cancer."
The researchers also found that a small segment of Mesd has the same effect as the larger molecule. This segment, or peptide, is more stable than the whole protein molecule and can be easily synthesized.
The researchers have patented the protein and the peptide through the university's Office of Technology Management. Recently, Raptor Pharmaceutical Corp. licensed Mesd from the university to develop it for clinical use.
Funding from the National Institutes of Health and the Siteman Cancer Center supported this research.
Got Hope? TNBC patients do now!
Doctors Review PARP
"I believe that in the next two to three years, PARP inhibitors will do for triple-negative breast cancer what trastuzumab [Herceptin] did for HER2 breast cancer." Jenny Chang, Baylor
"This development may have the potential to change patient survival . . . and appears to potentially change the natural history of at least a subclass of metastatic breast cancer [TNBC]" Clifford Hudis, MSK
“When you go home, be excited. Be really excited about this. Tell your patients there is reason to be hopeful.” Eric Winer, Dana Farber
Until now, the treatment for triple negative breast cancer has been limited. The options for metastatic patients were few and far between. Until now. The first completed studies of PARP, have shown that not only does it slow progression of disease, but patients are experiencing a complete response to the drug.
The side effects of PARP are generally well tolerated and do not include hair loss.
Where once there was no hope, no magic drug for triple negative patients, PARP is proving itself to be, as Dr. Jenny Chang, of the Baylor School of Medicine said, “What Herceptin did for HER2 breast cancer.”
“Many experts have argued that it is not possible to change survival in stage IV breast cancer. Certainly now there evidence for an alternative viewpoint; that with the use of very effective drugs, we can change overall survival, and we should aim for that." Clifford Hudis, MSK
For more information, speak to your oncologist. For information on recruiting trials for PARP click the following links:
http://clinicaltrials.gov/ct2/show/NCT00664781?term=PARP&rank=3
http://clinicaltrials.gov/ct2/show/NCT00516724?term=PARP&rank=4
http://clinicaltrials.gov/ct2/show/NCT00647062?term=PARP&rank=6
Sources:
Chang C. Interview with Neil Love. in Conversations with Oncology Investigators - Bridging the Gap between Research and Patient Care. Breast Cancer Update 2009;8(6):3-6 [Track 5; with audio].
Hudis C. Interview by L Scott Zoeller 2009 Oct 21. Extended Survival With PARP Inhibitors Changes Expectations in Metastatic Breast Cancer. Viewpoints. In OncologySTAT 2009.
Carlson R. PARP Inhibitors Show Promise Against Metastatic Triple-Negative Breast Cancer in Early Studies. Oncol Times 2009;31(15):10-11.
Triple Negative Breast Cancer News: Genome Project
Background: Drug companies have developed an array of drugs to attack cancer and other conditions influenced by genetics, but it’s difficult to tell which patients will respond to which drugs.
What’s happening: A new study will sequence the genomes of cancer tissue from 14 breast cancer patients whose tumors have progressed despite multiple treatments.
The future: Proponents of “genomic medicine” think it will become increasingly possible to use sequencing to steer individual patients to the drugs most likely to work.
A Carlsbad biotechnology company is helping launch an unusual cancer study that may eventually lead to doctors tailoring treatments to patients’ genes. Life Technologies says the study — involving sequencing the genomes of 14 patients with a tough-to-treat form of breast cancer — is a step toward a future of “genomic medicine,” a decade after the sequencing of the first human genome.
It’s evidence of how quickly work in this area is progressing, with the $2.6 billion that went into the Human Genome Project reduced to $6,000 per genome on Life Technologies’ latest sequencing instrument. “This is a pretty amazing example of how far these tools of genomics are moving into direct patient applications,” said Jeffrey Trent, president of the Phoenix-based Translational Genomics Research Institute, which is working with Life Technologies on the project.
The company will announce the study today to coincide with the opening of a two-day conference on genomic medicine in La Jolla, at which experts will discuss the latest breakthroughs and the outlook for more advances in the field. Already, biotechnology research has created numerous drugs that target genetic problems that lead to cancer and other conditions. In the case of breast cancer, at least a dozen such drugs are on the market, said Dr. Daniel D. Von Hoff, physician-in-chief at the translational genomics institute. A big problem, however, is that it’s difficult to predict which drugs will work for a particular patient. That’s where sequencing is supposed to help.
“For those mutations for which we do have drugs, we can help the physician make more informed decisions than they’re making today,” said Linh Hoang, director of personalized medicine at Life Technologies.
The study could also help scientists identify promising areas to explore for future drugs. It’s impossible to know ahead of time whether the 14 patients have genetic patterns that current drugs address, but researchers will also look for similarities in the DNA of the 14.
“It may lead to more targets that pharmaceutical companies will want to design drugs around,” Hoang said.
The study will involve patients with what’s known as triple-negative breast cancer whose tumors have progressed despite multiple therapies. That type of cancer makes up about a fifth of breast cancer cases and doesn’t respond to common drugs, such as Herceptin. Patients will be enrolled by U.S. Oncology, a Houston-area company that specializes in cancer-treatment services, and Von Hoff said the plan is to take the first 14 people who meet the study criteria.
A spokeswoman for U.S. Oncology said the company plans to enroll patients from about a half-dozen of its sites with the highest incidences of triple-negative cases. Sites in Colorado, Oregon, Texas and Virginia have already been identified.
Tissue samples will be obtained through noninvasive surgery, Von Hoff said. Then the patients will go home to await sequencing results that should be produced within a few weeks.
The idea is to then direct them to appropriate treatment, but Von Hoff declined to predict in how many cases that will be possible. “We don’t know,” Von Hoff said. “We do know there are more and more drugs out there forpatients who have mutations.”
There have been other studies that sequenced disease tumors, most notably an ongoing government effort known as the Cancer Genome Atlas that aims to produce comprehensive genetic maps of at least 20 types of cancer.
What separates the new study is its attempt use the data to drive treatment strategies, not merely to collect information “It’s a different question,” the genomics institute’s Trent said. “This is a study about how we’re going to start to use this in a precision medicine approach.”
A big effort will go into “bioinformatic” analysis, which Von Hoff said will involve a trillion pieces of data per patient. Hoang said one project in lung cancer found 30,000 mutations.
In coming years, scientists expect the cost of sequencing to decline and the sophistication of the tools to improve to the point that sequencing becomes more viable as a diagnostic device.
Hoang said Life Technologies expects the cost of the reagent chemicals that it sells, which enable genome sequencing, to drop from $6,000 to $3,000 by the end of the year. “This is really laying the foundation for a future that may take five or 10 years to materialize,” Hoang said. “But it is truly groundbreaking.”
Thomas Kupper, The Union Tribune, Uniontrib.com
The No Surrender Breast Cancer Foundation is blessed to have Constantine Kaniklidis to report to us from the front lines of breast cancer research and treatment advances. This is one of the most exciting and hopeful breakthroughs we have ever been able to provide our readers.
For all women who have triple negative breast cancer,
this is the hope we have been waiting for.
By Constantine Kaniklidis
Major Breakthrough in the Treatment of Triple Negative Breast Cancer
Commentary: Missed, and New, Opportunities
My own sense of the ASCO BSI-201 PARP trial is that on the contrary that it may have underestimated the true benefit; this perspective stems from my own TNBC review and research which on the cumulative evidence suggests that maximal benefit of PARP inhibition is accrued when it is concurrent with a strongly genotoxic (DNA-damaging) regimen, and although carboplatin is genotoxic, as are all platinum agents, gemcitabine (Gemzar) is not, and I believe this represents a lost opportunity. Indeed, I have on several occasions advocated in this context the omission of gemcitabine (Gemzar) altogether in the PARP context, in favor either of (1) a more optimal dose of carboplatin - I consider carboplatin AUC=2 as substantially sub-optimal, and would have deployed at least AUC=6 even up to AUC=7.5, or (2) substituting another genotoxic agent instead of gemcitabine (Gemzar), my choice being an anthracycline (preferably the pegylated liposomal Doxil or Caelyx. Given this limitation - which in all fairness the principal investigator Joyce O'Shaughnessy has acknowledged (due to expediency, not oversight) - of the failure to maximize the potential synergy of genotoxicity and PARP inhibition, in my mind therefore the trial's findings are actually therefore even more impressive by extrapolation, ad I would predict that an all-genotoxic chemotherapy + PARP inhibitor (BSI-201) will achieve significantly greater outcome benefit than even doubling of survival and halving of mortality for metastatic TNBC patients.
And this is where the opportunity can be regained, in the earlier availability of BSI-201 by this year's end, since at that point clinicians are no longer constrained to conform to the trial protocol's chemotherapy regimen, and I would advocated for them to instead adopt a more optimal all-genotoxic regimen which should translate to even more dramatic outcome gains. I am also of the opinion for molecular and other reasons that the failure of response of the PARP inhibitor regimen for some patients may be due in part to the absence of pure genotoxicity in the combination regimen, which therefore I am hoping innovative oncologists will recognize and overcome through appropriate DNA-damaging agent substitutions for the non-genotoxic gemcitabine (Gemzar) component, allowing more patients to be responsive to this breakthrough for metastatic TNBC disease.
Come The Revolution
Finally, remember the last time we heard of a 50% gain in breast cancer survival? That was with the revolutionary, practice-changing (virtually overnight) findings from Dennis Slamon's trial on trastuzumab (Herceptin) for HER2-positive disease, heralded correctly as the greatest breakthrough in breast cancer treatment since tamoxifen 30+ years ago. I believe an optimally genotoxic PARP inhibitor therapy can do for triple negative disease what Herceptin did for HER2+ patients, and the provisional results of the Phase III PARP Inhibitor to date appear to support and imply that contention.
These are the kind of times that researchers like me - and dedicated and brilliant investigators, and soon also patients - live to see as their reward for their commitment.
- Constantine Kaniklidis
We have been encouraging No Surrender readers to take their Vitamin D since our inception. Now, a study we have been following, has yielded great results- especially if you have triple negative breast cancer. We recommend Vitamin D supplementation no matter what your receptors are and suggest that women who do not have breast cancer also supplement to keep their D levels in good range.
Vitamin D Holds Promise in Battling a Deadly Breast Cancer
Wed, 2013-01-23 11:34
In research published in the Jan. 21 issue of The Journal of Cell Biology, a team led by Susana Gonzalo, PhD, assistant professor of biochemistry and molecular biology at Saint Louis University, has discovered a molecular pathway that contributes to triple-negative breast cancer, an often deadly and treatment resistant form of cancer that tends to strike younger women. In addition, Gonzalo and her team identified vitamin D and some protease inhibitors as possible new therapies and discovered a set of three biomarkers that can help to identify patients who could benefit from the treatment.
In the recent breakthrough, which was funded in part by a $500,000 Department of Defense grant, Gonzalo’s lab identified one pathway that is activated in breast cancers with the poorest prognosis, such as those classified as triple-negative. These cancers often strike younger women and are harder to treat than any other type of breast cancer. Women who are born with BRCA1 gene mutations are at increased risk for developing breast and ovarian cancers within their lifetime, and the tumors that arise are frequently the triple-negative type. Although chemotherapy is the most effective treatment for triple-negative breast cancer, it has profound secondary effects. Understanding the biology of triple-negative breast cancers will help to develop less toxic therapeutic strategies.
Experiments performed in Gonzalo's laboratory, in collaboration with the laboratories of Xavier Matias-Guiu and Adriana Duso (IRBLleida, Spain), showed that activation of this novel pathway not only allows tumor cells to grow unchecked, but also explains the reduced sensitivity of these types of tumors to current therapeutic strategies. Importantly, vitamin D plays a role in turning off this pathway, providing a safe and cost-effective strategy to fight these types of tumors.
For molecular biologists like Gonzalo who look for answers below the cellular level to discover why some people develop cancer, the search often involves tracing a chain of events to try to understand cause and effect of the behavior between several genes and the proteins which they express. In order to understand these complex pathways, researchers often turn levels of proteins on or off by expressing one gene or suppressing another. Part of a researcher’s challenge is determining what the function of each component of a pathway is.
The cell employs a complex mechanism to protect genetic information and ensure that damaged DNA is not passed on to daughter cells. Cells have built in checkpoints and fail safes to ensure the accuracy of their DNA code and are able to slow or stop their own proliferation if the information is compromised. Loss of these checkpoints and the accumulation of damaged DNA often leads to cancer.
BRCA1 is a well-established tumor suppressor gene. Women who carry mutations in this gene have a high risk of developing breast and ovarian cancer. Tumors that arise often lack expression of three receptors: estrogen, progesterone and HER2 (thus, “triple-negative”), and do not respond to hormone therapy.
BRCA1 is important because it is involved in repairing DNA double-strand breaks, a kind of DNA damage that is especially dangerous for the integrity of our genome. BRCA1 also is involved in cell-cycle checkpoints after damage, which are control mechanisms during cell proliferation that make sure the DNA information has been accurately replicated and transferred to the daughter cells. Thus, BRCA1 is considered a safeguard of the genome.
Loss of BRCA1 is bad news for the information contained in a cell’s genetic blueprint. It results in genomic instability characterized by unrepaired DNA breaks and chromosomal aberrations that compromise cell viability. How BRCA1-mutated cells are able to form tumors has been a long-standing question. Investigators recently showed that loss of another DNA repair factor, 53BP1, allows proliferation and survival of BRCA1-deficient cells. In addition, decreased levels of 53BP1 were observed in triple-negative breast cancers, and correlated with resistance to drugs at the forefront of cancer treatment, such as PARP inhibitors.
Gonzalo’s team has found a pathway responsible for the loss of 53BP1 in breast cancers with poor prognosis, specifically BRCA1 mutated and triple-negative. It turns out that loss of BRCA1 increases the expression of a protease, known as cathepsin L (CTSL), which causes the degradation of 53BP1. Cells that have lost both BRCA1 and 53BP1 have the ability to repair DNA, maintain the integrity of the genome, and proliferate. Thus, the protease helps cells with faulty BRCA1 to survive.
If lowering the levels of 53BP1 allows BRCA1 deficient cells to thrive and do their worst, increasing the levels of the protein offers a promising strategy for treatment of breast tumors.
So, how to do this? In previous research, Gonzalo’s team showed that vitamin D inhibits CTSL-mediated degradation of 53BP1 in non-tumor cells, as efficiently as specific CTSL inhibitors. This time, they found that treatment of BRCA1-deficient tumor cells with vitamin D restores high levels of 53BP1, which results in increased genomic instability and reduced proliferation.
Importantly, their evidence suggests that vitamin D treatment might restore the sensitivity to PARP inhibitors in patients who become resistant. Thus, a combination of vitamin D and PARP inhibitors could represent a novel therapeutic strategy for breast cancers with poor prognosis.
So, with this chain of events, Gonzalo and colleagues demonstrated a pathway by which triple-negative breast cancers proliferate: BRCA1-deficient cells activate CTSL which minimizes levels of 53BP1 to overcome genomic instability and growth arrest.
In a final exceptionally useful discovery, Gonzalo and collaborators found that high levels of nuclear CTSL and low levels of 53BP1 and nuclear vitamin D receptor (VDR) are a clear marker that identifies certain triple-negative breast cancer patients, biomarkers that offer the potential to customize future breast cancer therapies. In particular, this triple-biomarker signature will allow the identification of patients in whom the pathway is on and who might benefit the most from vitamin D treatment.
From OncologyNurseAdvisor
January 14, 2013
Newfound marker for aggressive breast cancer may also be a treatment target
The findings of a recent study strongly implicate the ribonucleic acid (RNA) molecule miR-181a as a predictive biomarker for breast cancer metastasis and patient survival, which in turn makes the molecule a potential therapeutic target in metastatic breast cancer.
As explained in a statement issued by Case Western Reserve University in Cleveland, Ohio, miR-181a had never before been tied to breast cancer metastasis. However, William P. Schiemann, PhD, of the Case Comprehensive Cancer Center, and colleagues found elevated levels of the molecule in late-stage breast cancer tissues.
The investigators described in The Journal of Clinical Investigation (2013;123[1]:150-163) their discovery that miR-181a expression was essential in driving metastasis and enhancing the lethality of late-stage mammary tumors in mice. In addition, miR-181a expression was dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and was highly predictive for decreased overall survival in humans with breast cancer.
An inhibitor of miR-181a tested in the mice prevented metastasis and extended survival.
“Overall, these findings reinforce our belief that the discovery of miR-181a will become a strong predictive biomarker for breast cancer metastasis, and that the high expression of miR-181a in tumor tissues will pave the way for the development of targeted therapies, better prognosis, and increased patient survival,” commented Schiemann in the Case Western statement.
Septemner 6, 2012
UT MD Anderson Cancer Center Launches Unprecedented Moon Shots Program
Effort sets new bar for eradicating cancer; Goal to significantly increase patient survival during the next decade
HOUSTON — The University of Texas MD Anderson Cancer Center announces the launch of the Moon Shots Program, an unprecedented effort to dramatically accelerate the pace of converting scientific discoveries into clinical advances that reduce cancer deaths.
Even as the number of cancer survivors in the US is expected to reach an estimated 11.3 million by 2015, according to the American Cancer Society, cancer remains one of the most destructive and vexing diseases. An estimated 100 million people worldwide are expected to lose their lives to cancer in this decade alone. The disease’s devastation to humanity now exceeds that of cardiovascular disease, tuberculosis, HIV and malaria – combined.
The Moon Shots Program is built upon a “disruptive paradigm” that brings together the best attributes of both academia and industry by creating cross-functional professional teams working in a goal-oriented, milestone-driven manner to convert knowledge into tests, devices, drugs and policies that can benefit patients as quickly as possible.
The Moon Shots Program takes its inspiration from President John Kennedy’s famous 1962 speech, made 50 years ago this month at Rice University, just a mile from the main MD Anderson campus. “We choose to go to the moon in this decade ... because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win,” Kennedy said.
“Generations later, the Moon Shots Program signals our confidence that the path to curing cancer is in clearer sight than at any other time in history,” said Ronald A. DePinho, M.D., MD Anderson’s president. “Humanity urgently needs bold action to defeat cancer. I believe that we have many of the tools we need to pick the fight of the 21st century. Let’s focus our energies on approaching cancer comprehensively and systematically, with the precision of an engineer, always asking ... ‘What can we do to directly impact patients?’”
The inaugural moon shots
The program, initially targeting eight cancers, will bring together sizable multidisciplinary groups of MD Anderson researchers and clinicians to mount comprehensive attacks on:
- acute myeloid leukemia/myelodysplastic syndrome;
- chronic lymphocytic leukemia;
- melanoma;
- lung cancer;
- prostate cancer, and
- triple-negative breast and ovarian cancers – two cancers linked at the molecular level.
Six moon shot teams, representing these eight cancers, were selected based on rigorous criteria that assess not only the current state of scientific knowledge of the disease across the entire cancer care continuum from prevention to survivorship, but also the strength and breadth of the assembled teams and the potential for near-term measurable success in terms of cancer mortality.
Each moon shot will receive an infusion of funds and other resources needed to work on ambitious and innovative projects prioritized for patient impact, ranging from basic and translational research to biomarker-driven novel clinical trials, to behavioral interventions and public policy initiatives.
The platforms make the program unique
The institution-wide, high quality scientific and technical platforms will provide key infrastructure for the success of the Moon Shots Program. In the past, each investigator or group of investigators has developed their own infrastructure to support their research programs. Frequently they were under-funded and lacked the high level management and leadership required to ensure that they were of the highest caliber and in particular that they were able to adapt to the rapidly changing scientific and technological environment. The moon shot platforms will be designed and resourced to provide expertise that will support the efforts of all of moon shots teams. The platforms will provide a critical component to the success of each moon shot and of the overall Moon Shots Program. In particular, they will leverage the investment across the moon shots.
These platforms include:
Adaptive Learning in Genomic Medicine: A work flow that enables clinicians and researchers to integrate real-time patient clinical information and research genomic data, allowing understanding of the cancer genome and ultimately improving outcome.
Big Data: The capture, storage and processing of huge amounts of information, much of it coming from Next Generation Sequencing machines (genome sequencing).
Cancer Control and Prevention: Community-based efforts in cancer prevention, screening, and early detection and survivorship to educate and achieve a measureable reduction in the cancer burden. Interventions in the areas of public policy, public education, professional education and evidence-based service delivery can make a measurable and lasting difference in our community, especially among those most vulnerable - the underserved.
Center for Co-Clinical Trials: Uses mouse or cell models of human cancers to test new drugs or drug combinations and discover the subset of patients most likely to respond to the therapy.
Clinical Genomics: An infrastructure designed to bank and process tumor specimens for clinical tests that can guide medical decisions.
Diagnostics Development: The development of diagnostic tests for use in the clinic to guide targeted therapy.
Early Detection: Using imaging and proteomic technologies to discover markers that can identify patients with early-staged cancers.
Institute for Applied Cancer Science: Developing effective targeted cancer drugs.
Institute for Personalized Cancer Therapy: An extensive infrastructure that analyzes genomic abnormalities in patient tumors to direct them to the best treatments and clinical trials.
Massive Data Analytics: A computer infrastructure that develops or uses computational algorithms to analyze large-scale patient and public data.
Patient Omics: Centralizing collection of patient biospecimens (tumor samples, blood, etc.) to profile genes and proteins (genomics, proteomics) and identify mutations that can guide personalized treatment decisions and predict therapy-related toxicity to improve overall patient outcomes.
Translational Research Continuum: A framework to facilitate efficient transition of a candidate drug from preclinical studies to early stages of human clinical trial testing so effective drugs can be developed in a shorter time and clinical trials can be quicker and cheaper with higher success rates.
MD Anderson’s “Giant leap for mankind”
A year ago, when DePinho was named MD Anderson’s fourth president, he proposed the notion of a moon shot moment. “How can we envision what’s possible to reduce cancer mortality if we think boldly, adopt a more goal-oriented mentality, ignore the usual strictures on resources that encumber academic research and use the breakthrough technology available today?” he asked. Response from the faculty and staff took the form of initial moon shot proposals that targeted several major cancer types and involved large, integrated MD Anderson teams, sometimes numbering in the hundreds.
Frank McCormick, Ph.D., director of the University of California, San Francisco Cancer Center and president of the American Association for Cancer Research, led the review panel of 25 internal and external experts that narrowed the field to the inaugural six moon shots.
“Nothing on the magnitude of the Moon Shots Program has been attempted by a single academic medical institution,” McCormick said. “Moon shots take MD Anderson’s deep bench of multidisciplinary research and patient care resources and offer a collective vision on moving cancer research forward.”
McCormick added, “The process of bringing this amount of horsepower together in such a focused manner is not normally seen in academic medicine and is valuable in and of itself.”
“The Moon Shots Program holds the potential for a new approach to research that eventually can be applied to all cancers and even to other chronic diseases,” DePinho said. “History has taught us that if we put our minds to a task, the human spirit will prevail. We must do this – humanity is depending on all of us.”
For more information, including backgrounders on the inaugural moon shots, please visit www.cancermoonshots.org
February, 2011
STATEMENT ON ACCESS TO THE INVESTIGATIONAL AGENT INIPARIB
Many patients and advocates within the breast cancer community have been following Sanofi’s research on the investigational agent iniparib for the last several years, in the hopes that it might eventually provide a new treatment option for the patients battling metastatic triple negative breast cancer (mTNBC). However, Sanofi recently reported in February 2011, that the
Phase III study of iniparib in combination with gemcitabine and carboplatin, in patients with mTNBC, did not demonstrate an improvement in either progression‐ free survival or overall survival when compared to gemcitabine and carboplatin alone.
As such, the data from this Phase III study do not support an application for approval by the U.S. Food & Drug Administration (FDA). After extensive discussions with the FDA and external breast cancer experts – including several patient advocacy organizations – Sanofi has decided that it is
necessary to initiate new clinical studies of iniparib, in an effort to better understand how the agent works and to identify potential dosing and patient populations.
In the light of the Phase III results and the need to further investigate iniparib, Sanofi and BiPar Sciences have decided to close the current Expanded Access Program (EAP) for all new patient enrollment effective as of August 15, 2011.
In addition, Sanofi and BiPar Sciences recommend that patients currently receiving iniparib (BSI‐201) as part of the EAP discontinue treatment under this program. However, physicians may consider continuing iniparib in combination with gemcitabine and carboplatin, based on the assessment of individual patients. If the decision is made to continue iniparib, the patient needs to be re‐consented.
All patients screened and deemed eligible for the EAP will be allowed to enter into the program until August 15, 2011. Since all eligible patients will be selected during this time, the random selection process administered by the National Organization for Rare Disorders (NORD)
has been discontinued. Enrollment criteria will still be confirmed for patient entry. As before, the patient’s physician will receive email notification when it is acceptable for them to proceed with treatment.
At Sanofi and Bipar Sciences, we feel that closing this EAP – while difficult – is the most responsible course of action, since the clinical benefit of iniparib has not been demonstrated. Additionally, we do not want the iniparib EAP to inadvertently prevent mTNBC patients from accessing other treatment options or participating in clinical trials of other investigational agents.
Patients who are interested in finding out more about clinical trials are encouraged to visit http://www.clinicaltrials.gov.
Sanofi remains committed to advancing the field of breast cancer research by continuing to study iniparib. To this end, Sanofi will be initiating the new iniparib clinical research program in the breast cancer setting in the next few weeks.
Patient & Patient Advocate Q&A
1. If I participated in an iniparib clinical trial and still receive it, will I be able to continue receiving iniparib from the company?
If you are receiving iniparib as a result of your participation in a metastatic triple negative breast cancer (mTNBC) clinical trial and your physician feels that it is appropriate for you to continue receiving iniparib, we do not anticipate any disruption in your access to iniparib, regardless of
whether you are receiving it in the 1st, 2nd, or 3rd line setting.
2. If I am a mTNBC patient currently enrolled in the Expanded Access Program (EAP), will I continue to receive Iniparib?
Yes, if you are already enrolled in the EAP you will continue to receive iniparib through the EAP, until your physician feels it is no longer appropriate. All patients continuing to receive iniparib through the EAP must sign a new consent form, however.
3. If I am a mTNBC patient waiting to be enrolled in the EAP, can I still get in?
Yes, if you are a 2nd, 3rd, or 4th line patient, you will be able to enroll in the EAP until August 15, 2011. Based on the analysis of the Phase III data, we are no longer accepting new 1st line patients into the EAP, because the trial did not demonstrate that iniparib provided a benefit for patients taking iniparib.
After August 15, 2011 , Sanofi will no longer be enrolling any new patients in the program, regardless of line of therapy, due to the negative Phase III study results.
All patients screened and deemed eligible for the EAP will be allowed to enter into the program until August 15, 2011. Since all eligible patients will be selected during this time, the random selection process administered by the National Organization for Rare Disorders (NORD)
has been discontinued. Enrollment criteria will still be confirmed for patient entry. As before, the patient’s physician will receive email notification when it is acceptable for them to proceed with treatment.
Sanofi remains committed to advancing the field of breast cancer research by continuing to study iniparib.
4. What is the timing for the discontinuation of the current EAP program and the initiation of the new clinical trial program?
The EAP will no longer be open for patient enrollment after August 15, 2011. While we are still finalizing the protocol for the new Phase 1B clinical trial of iniparib, we anticipate that it will begin enrolling patients in within the next few weeks. For more information on this study or other clinical trials, please visit www.clinicaltrials.gov.
5. Will the iniparib EAP program continue to enroll patients after the initiation of the new clinical trial program?
No. Providing access to an investigational agent through an EAP can make it very difficult – if not impossible – to simultaneously enroll a clinical trial that is designed to evaluate the same investigational agent.
Additionally, in light of the need to make significant changes to iniparib’s clinical development program, the company does not feel it is appropriate to continue the Expanded Access Program (EAP) when so many important questions about iniparib remain unanswered. Therefore, Sanofi
will be closing the EAP to new patient enrollment after August 15, 2011.
Patients currently enrolled in the EAP will be permitted to remain in the program until their disease progresses or their physicians feel they are no longer receiving benefit from iniparib, as long as they sign a new consent form.
Natural Weapon Against Triple Negative Breast Cancer
Something so simple.... nature healing nature.... Will this be the answer like mold was to penicillin?
Oncolytic Virus Kills Tumor in Triple-Negative Breast Cancer
Caroline Helwick, Medscape
October 25, 2011 (San Francisco, California) — Laboratory studies conducted at the Memorial Sloan-Kettering Cancer Center in New York City suggest that triple-negative breast cancer (TNBC) might respond to treatment with an oncolytic agent.
The findings were reported here at the American College of Surgeons 97th Annual Clinical Congress.
"We found that [the mutant herpes virus] NV1066 is an effective oncolytic agent against triple- negative breast cancer in vitro and in vivo," said Sepideh Gholami, MD, a research fellow in the laboratory of Yuman Fong, MD, which is considered to be at the forefront in oncolytic viral therapy
research.
"Oncolytic viruses are attractive therapeutic agents that destroy tumor cells without the accompanying destruction of normal cells," she said. The mitogen-activated protein kinase (MAPK)signaling pathway is known to be important in TNBC, and activated (phosphorylated) MAPK signaling has been shown to mediate efficient replication of NV1066 through the deletion of the delta gamma(1)34.5 gene.
In other words, she said, TNBC cells have high levels of phosphorylated MAPK, a protein that promotes tumor growth and contributes to resistance to current therapies. The herpes virus specifically targets cells that overexpress this protein, which is the rationale for this approach. The study aimed to determine whether NV1066 could kill TNBC cells effectively. The researchers also examined the functional effects of NV1066 on the MAPK signal transduction pathway during viral infection.
Dr. Gholami and colleagues infected 5 different TNBC cell lines with the NV1066 herpes simplex virus. After treatment with the virus, the most sensitive cell lines demonstrated a 90% cell kill rate within 1 week; the less sensitive lines demonstrated a 70% cell kill rate.
In addition, sensitive cell lines expressed higher baseline levels of phosphorylated MAPK than resistant cell lines, and viral infection caused the downregulation of phosphorylated MAPK by 48 hours, she reported.
"TNBC cells support efficient viral replication, with over 1 million copy numbers observed, which is more than a 1000-fold increase," she said.
"Since baseline phosphorylated MAPK levels positively correlated with sensitivity to NV1066, they might therefore be used as a clinical marker for selecting patients for viral therapy," she suggested.
Tumor Regression Almost Complete
The researchers created flank tumors and injected them with NV1066 or a control compound. Within 5 days, tumor volume significantly decreased in the experimental group; within 3 weeks, they observed "near-complete tumor regression," Dr. Gholami reported.
....keep reading for more good news below!
NEW Targeted Drug Seeks and Destroys TNBC...
This could be big. Breast cancer is not one disease as we all know. Triple Negative Breast Cancer has been on the back burner in terms of new therapies, until now. PARP treatment is changing the future of metastatic TNBC patients. Now, a new, targeted therapy has identified a sub-type of TNBC tumors...
New Subtype of Breast Cancer Responds to Targeted Drug
ScienceDaily (Mar. 2, 2010) — A newly identified cancer biomarker could define a new subtype of breast cancer as well as offer a potential way to treat it, say researchers at Washington University School of Medicine in St. Louis.
Their findings will be published in the March 1 online early edition issue of the Proceedings of the National Academy of Sciences.
The research could further refine what recent breast cancer research has concluded: that breast cancer is not one disease, but many. So far, research has firmly established that at least five subtypes of breast cancer exist, each having distinct biological features, clinical outcomes and responses to traditional therapies.
The biomarker identified by the Washington University researchers is found frequently in breast cancers and especially in those that have poorer outcomes. It stems from overactivation of a gene called LRP6 (low-density lipoprotein receptor-related protein 6), which stimulates an important cell-growth signaling pathway. LRP6 can be inhibited by a protein discovered in the same laboratory, which could become an effective drug against the breast cancer type, the researchers say.
"We found increased expression of the LRP6 gene in about a quarter of breast cancer specimens we examined, and we think LRP6 overexpression could be a marker for a new class of breast cancer," says Guojun Bu, Ph.D., professor of pediatrics and of cell biology and physiology. "In addition, we found that this biomarker is often associated with breast cancers that are either harder to treat or more likely to recur. We already have an agent that seems to be effective against LRP6-overexpressing tumors, which could someday become a therapy for tumors that right now have few treatment options."
The research was conducted primarily by Chia-Chen Liu, a graduate student in the Bu lab, who is a fellow in the Cancer Biology Pathway Program at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.
The researchers' analysis of human breast cancer tissue samples found significant increases in LRP6 levels in 20 percent to 36 percent of the tumors. LRP6 was increased more frequently in ER (estrogen receptor)-negative or HER2 (human epidermal growth factor receptor 2)-negative samples. LRP6 was also increased more frequently in so-called triple-negative breast tumor samples, which test negative for ER, HER2 and PR (progesterone receptor).
In general, patients who have triple-negative breast cancers have an increased risk of disease recurrence after initial treatment and a poorer prognosis. Furthermore, although ER-positive and HER2-positive tumors can be targeted with specific therapies, ER-negative and HER2-negative tumors cannot. So it appears that LRP6 overexpression is often associated with tumors that are currently difficult to treat, says Bu.
Research in the lab had earlier discovered a protein that binds to and inhibits LRP6. This study showed that the protein, called Mesd (mesoderm development), was able to slow the growth of breast cancer cells in the laboratory and to inhibit mammary tumor growth in laboratory mice.
Importantly, mice treated with Mesd did not experience any of the known side effects, such as bone lesions, skin disorders or intestinal malfunctions, associated with inhibition of this growth pathway.
"Our work introduces Mesd as a promising antitumor agent that might be further developed for breast cancer therapy," Bu says. "It would be analogous to such successful breast cancer therapies as Herceptin (trastuzumab), which specifically targets HER2-positive breast cancer."
The researchers also found that a small segment of Mesd has the same effect as the larger molecule. This segment, or peptide, is more stable than the whole protein molecule and can be easily synthesized.
The researchers have patented the protein and the peptide through the university's Office of Technology Management. Recently, Raptor Pharmaceutical Corp. licensed Mesd from the university to develop it for clinical use.
Funding from the National Institutes of Health and the Siteman Cancer Center supported this research.
Got Hope? TNBC patients do now!
Doctors Review PARP
"I believe that in the next two to three years, PARP inhibitors will do for triple-negative breast cancer what trastuzumab [Herceptin] did for HER2 breast cancer." Jenny Chang, Baylor
"This development may have the potential to change patient survival . . . and appears to potentially change the natural history of at least a subclass of metastatic breast cancer [TNBC]" Clifford Hudis, MSK
“When you go home, be excited. Be really excited about this. Tell your patients there is reason to be hopeful.” Eric Winer, Dana Farber
Until now, the treatment for triple negative breast cancer has been limited. The options for metastatic patients were few and far between. Until now. The first completed studies of PARP, have shown that not only does it slow progression of disease, but patients are experiencing a complete response to the drug.
The side effects of PARP are generally well tolerated and do not include hair loss.
Where once there was no hope, no magic drug for triple negative patients, PARP is proving itself to be, as Dr. Jenny Chang, of the Baylor School of Medicine said, “What Herceptin did for HER2 breast cancer.”
“Many experts have argued that it is not possible to change survival in stage IV breast cancer. Certainly now there evidence for an alternative viewpoint; that with the use of very effective drugs, we can change overall survival, and we should aim for that." Clifford Hudis, MSK
For more information, speak to your oncologist. For information on recruiting trials for PARP click the following links:
http://clinicaltrials.gov/ct2/show/NCT00664781?term=PARP&rank=3
http://clinicaltrials.gov/ct2/show/NCT00516724?term=PARP&rank=4
http://clinicaltrials.gov/ct2/show/NCT00647062?term=PARP&rank=6
Sources:
Chang C. Interview with Neil Love. in Conversations with Oncology Investigators - Bridging the Gap between Research and Patient Care. Breast Cancer Update 2009;8(6):3-6 [Track 5; with audio].
Hudis C. Interview by L Scott Zoeller 2009 Oct 21. Extended Survival With PARP Inhibitors Changes Expectations in Metastatic Breast Cancer. Viewpoints. In OncologySTAT 2009.
Carlson R. PARP Inhibitors Show Promise Against Metastatic Triple-Negative Breast Cancer in Early Studies. Oncol Times 2009;31(15):10-11.
Triple Negative Breast Cancer News: Genome Project
Background: Drug companies have developed an array of drugs to attack cancer and other conditions influenced by genetics, but it’s difficult to tell which patients will respond to which drugs.
What’s happening: A new study will sequence the genomes of cancer tissue from 14 breast cancer patients whose tumors have progressed despite multiple treatments.
The future: Proponents of “genomic medicine” think it will become increasingly possible to use sequencing to steer individual patients to the drugs most likely to work.
A Carlsbad biotechnology company is helping launch an unusual cancer study that may eventually lead to doctors tailoring treatments to patients’ genes. Life Technologies says the study — involving sequencing the genomes of 14 patients with a tough-to-treat form of breast cancer — is a step toward a future of “genomic medicine,” a decade after the sequencing of the first human genome.
It’s evidence of how quickly work in this area is progressing, with the $2.6 billion that went into the Human Genome Project reduced to $6,000 per genome on Life Technologies’ latest sequencing instrument. “This is a pretty amazing example of how far these tools of genomics are moving into direct patient applications,” said Jeffrey Trent, president of the Phoenix-based Translational Genomics Research Institute, which is working with Life Technologies on the project.
The company will announce the study today to coincide with the opening of a two-day conference on genomic medicine in La Jolla, at which experts will discuss the latest breakthroughs and the outlook for more advances in the field. Already, biotechnology research has created numerous drugs that target genetic problems that lead to cancer and other conditions. In the case of breast cancer, at least a dozen such drugs are on the market, said Dr. Daniel D. Von Hoff, physician-in-chief at the translational genomics institute. A big problem, however, is that it’s difficult to predict which drugs will work for a particular patient. That’s where sequencing is supposed to help.
“For those mutations for which we do have drugs, we can help the physician make more informed decisions than they’re making today,” said Linh Hoang, director of personalized medicine at Life Technologies.
The study could also help scientists identify promising areas to explore for future drugs. It’s impossible to know ahead of time whether the 14 patients have genetic patterns that current drugs address, but researchers will also look for similarities in the DNA of the 14.
“It may lead to more targets that pharmaceutical companies will want to design drugs around,” Hoang said.
The study will involve patients with what’s known as triple-negative breast cancer whose tumors have progressed despite multiple therapies. That type of cancer makes up about a fifth of breast cancer cases and doesn’t respond to common drugs, such as Herceptin. Patients will be enrolled by U.S. Oncology, a Houston-area company that specializes in cancer-treatment services, and Von Hoff said the plan is to take the first 14 people who meet the study criteria.
A spokeswoman for U.S. Oncology said the company plans to enroll patients from about a half-dozen of its sites with the highest incidences of triple-negative cases. Sites in Colorado, Oregon, Texas and Virginia have already been identified.
Tissue samples will be obtained through noninvasive surgery, Von Hoff said. Then the patients will go home to await sequencing results that should be produced within a few weeks.
The idea is to then direct them to appropriate treatment, but Von Hoff declined to predict in how many cases that will be possible. “We don’t know,” Von Hoff said. “We do know there are more and more drugs out there forpatients who have mutations.”
There have been other studies that sequenced disease tumors, most notably an ongoing government effort known as the Cancer Genome Atlas that aims to produce comprehensive genetic maps of at least 20 types of cancer.
What separates the new study is its attempt use the data to drive treatment strategies, not merely to collect information “It’s a different question,” the genomics institute’s Trent said. “This is a study about how we’re going to start to use this in a precision medicine approach.”
A big effort will go into “bioinformatic” analysis, which Von Hoff said will involve a trillion pieces of data per patient. Hoang said one project in lung cancer found 30,000 mutations.
In coming years, scientists expect the cost of sequencing to decline and the sophistication of the tools to improve to the point that sequencing becomes more viable as a diagnostic device.
Hoang said Life Technologies expects the cost of the reagent chemicals that it sells, which enable genome sequencing, to drop from $6,000 to $3,000 by the end of the year. “This is really laying the foundation for a future that may take five or 10 years to materialize,” Hoang said. “But it is truly groundbreaking.”
Thomas Kupper, The Union Tribune, Uniontrib.com
The No Surrender Breast Cancer Foundation is blessed to have Constantine Kaniklidis to report to us from the front lines of breast cancer research and treatment advances. This is one of the most exciting and hopeful breakthroughs we have ever been able to provide our readers.
For all women who have triple negative breast cancer,
this is the hope we have been waiting for.
By Constantine Kaniklidis
Major Breakthrough in the Treatment of Triple Negative Breast Cancer
- A recent updated analysis of the original BS-201 PARP Inhibitor (PARPi) Trial continues to show an exceptional outcome benefit to the addition of the PARP inhibitor (PARPi) BSI-201 to the gemcitabine-carboplatin chemotherapy backbone, and although these are interim and not final results which could change in either direction, at this time the interim findings support the provisional conclusion that the PARP inhibitor essentially - and amazingly - doubles overall survival (OS) - not just PFS (progression-free survival), also improved, meaning reduction in the risk of recurrence - in the triple negative breast cancer population, and at this time sustains a 50% reduction in the risk of death.
[Disclaimer: we must wait the final results of the trial to see if these dramatic, first-ever results, are sustained at the same or reasonably comparable levels as now seen with the interim findings]. - These rather stunning survival outcomes were furthermore accompanied by highly impressive response rates: the overall response rate (ORR) was high, at 48% of patients achieving complete response (CR) or partial response (PR) which is three times as high as that obtained with chemotherapy alone, and with another 14% achieving stable disease (SD, for 6 month or greater), yielding a clinical benefit rate (CBR) of 62% (CBR = CR + PR + SD), and with no significant additional adverse effects from the addition of BSI-201 to the chemotherapy backbone (impressive, remembering that non-toxic agents are notoriously hard to come by in oncology).
- The accrual and progress of the trial has proceeded at extremely rapid pace, well beyond expectations, and the best estimation, based on feedback from investigators, is that this Phase III trial given the pace, will come to completion as early as this (First) Quarter of 2010. Interview statements - but not officially posted NCI protocol data - suggests that there are just 40 patients remaining requiring trial accounting, 20 in the PARP inhibitor arm, and another 20 in the chemotherapy only arm, confirming that completion is very close, and that a First Quarter 2010 estimate is plausible on the progress to date.
- Finally, on the regulatory front it also appears there is accelerated progress: the PARP inhibitor BSI-201 has been granted on Fast Track Designation by the FDA, very good news for patients: FDA Fast Track means that, against standard requirements, the agency will accept initial late-stage data instead of waiting for entire Phase III clinical trial results, something that is done when (1) a proposed agent is intended for treatment of a serious or life-threatening disease - a status now accepted by the FDA for mTNBC (metastatic TNBC) - and (2) demonstrates the potential to address unmet needs for such a condition. Based on this status and on a review of documents filed in the FDA regulatory pipeline process, it is now estimated that BSI-201 may actually become commercially available - and hence available to all mTNBC patients in clinical practice without being on any clinical trial - at year's end (mid November to mid December, best estimate).
Commentary: Missed, and New, Opportunities
My own sense of the ASCO BSI-201 PARP trial is that on the contrary that it may have underestimated the true benefit; this perspective stems from my own TNBC review and research which on the cumulative evidence suggests that maximal benefit of PARP inhibition is accrued when it is concurrent with a strongly genotoxic (DNA-damaging) regimen, and although carboplatin is genotoxic, as are all platinum agents, gemcitabine (Gemzar) is not, and I believe this represents a lost opportunity. Indeed, I have on several occasions advocated in this context the omission of gemcitabine (Gemzar) altogether in the PARP context, in favor either of (1) a more optimal dose of carboplatin - I consider carboplatin AUC=2 as substantially sub-optimal, and would have deployed at least AUC=6 even up to AUC=7.5, or (2) substituting another genotoxic agent instead of gemcitabine (Gemzar), my choice being an anthracycline (preferably the pegylated liposomal Doxil or Caelyx. Given this limitation - which in all fairness the principal investigator Joyce O'Shaughnessy has acknowledged (due to expediency, not oversight) - of the failure to maximize the potential synergy of genotoxicity and PARP inhibition, in my mind therefore the trial's findings are actually therefore even more impressive by extrapolation, ad I would predict that an all-genotoxic chemotherapy + PARP inhibitor (BSI-201) will achieve significantly greater outcome benefit than even doubling of survival and halving of mortality for metastatic TNBC patients.
And this is where the opportunity can be regained, in the earlier availability of BSI-201 by this year's end, since at that point clinicians are no longer constrained to conform to the trial protocol's chemotherapy regimen, and I would advocated for them to instead adopt a more optimal all-genotoxic regimen which should translate to even more dramatic outcome gains. I am also of the opinion for molecular and other reasons that the failure of response of the PARP inhibitor regimen for some patients may be due in part to the absence of pure genotoxicity in the combination regimen, which therefore I am hoping innovative oncologists will recognize and overcome through appropriate DNA-damaging agent substitutions for the non-genotoxic gemcitabine (Gemzar) component, allowing more patients to be responsive to this breakthrough for metastatic TNBC disease.
Come The Revolution
Finally, remember the last time we heard of a 50% gain in breast cancer survival? That was with the revolutionary, practice-changing (virtually overnight) findings from Dennis Slamon's trial on trastuzumab (Herceptin) for HER2-positive disease, heralded correctly as the greatest breakthrough in breast cancer treatment since tamoxifen 30+ years ago. I believe an optimally genotoxic PARP inhibitor therapy can do for triple negative disease what Herceptin did for HER2+ patients, and the provisional results of the Phase III PARP Inhibitor to date appear to support and imply that contention.
These are the kind of times that researchers like me - and dedicated and brilliant investigators, and soon also patients - live to see as their reward for their commitment.
- Constantine Kaniklidis
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