Citizen Petition Requesting the FDA to Withdraw Approval of Adjuvant ACT Chemotherapy for BRCA1 Breast Cancer Patients (November 15, 2012)

Summary – This Petition provides the basis for the FDA to modify the industry-wide practice of administering ACT chemotherapy to BRCA1, triple-negative breast cancer victims because: a) there is little to no factual evidence to support its purported efficacy for this distinct subgroup; 2) there is reason to believe that it is disproportionately harmful to this subgroup of patients and 3) there are alternatives readily available for this subgroup with better results in clinical studies.


Dear Commissioner Margaret Hamburg, M.D.:

Every year about 15,000 women are diagnosed with BRCA1-related breast cancer. Most of these victims are triple-negative (i.e., lacking the three receptors that are identified for treating breast cancer). The standard treatment for triple-negative breast cancer patients, including the subgroup of BRCA 1 carriers, is prescribed with a powerful chemotherapy regime (typically an Anthracycline such as Adriamycin, a Cyclophosphamide such as Cytoxan, and a Taxane such as Taxol). Based on the findings documented below, the undersigned submits this Petition to request the FDA to categorize BRCA1-related breast cancer as a distinct group and to withdraw approval for the use of ACT as an adjuvant therapy for BRCA1-related breast cancer patients.

Summary of Findings

  1. Most BRCA-1 cancer patients are triple-negative. However, only about 15% of triple-negative breast cancer patients are BRCA1-related.
  2. BRCA1, triple-negative breast cancer and non-BRCA1, triple-negative breast cancer have different causes and different reactions to chemotherapy.
  3. Given these differences and the laws of statistical analyses, the results of any clinical trial of triple-negative patients cannot be applied with statistical validity to the BRCA 1 sub-category of triple-negative patients unless that sub-category is specifically separated out and monitored.
  4. There is little research that separates out the effects of ACT on BRCA1, triple-negative patients versus non-BRCA1, triple-negative patients.
  5. The National Cancer Institute’s website refers to only one study to support the use of adjuvant chemotherapy for the subgroup of BRCA1 triple-negative patients. However, as explained below, the reliance on that study is misplaced. In fact, the raw data in that study supports the opposite conclusion.
  6. Looking at the issue from another vantage point, two of the three drugs in the ACT chemotherapy regime cause DNA damage. BRCA1 carriers do not have the ability to repair double-strand DNA breaks, which can lead to the formation of cancerous tumors. Therefore, there is reason to believe that the use of ACT has an adjunctive therapy for BRCA1 patients may be creating disproportionate side effects for this subgroup of triple-negative patients.
  7. Finally, there are better alternatives available for BRCA1 breast cancer patients seeking adjuvant chemotherapy than ACT (e.g., PARP/platinum-based drugs).
  8. Accordingly, there is a sufficient basis for the FDA to modify the industry-wide practice of administering ACT chemotherapy to BRCA1, triple-negative breast cancer victims because: a) there is little to no factual evidence to support its purported efficacy for this distinct subgroup; 2) there is reason to believe that it is disproportionately harmful to this subgroup of patients and 3) there are alternatives readily available for this subgroup with better results in clinical studies.

Environmental Impact

The Petitioner claims a categorical exclusion under Part 25.30 of the FDA’s Administrative Practices and Procedures regarding the requirement to file an environment impact statement.

Documentation

Shortly after the discovery of the BRCA1 gene’s influence on breast cancer, scientists were able to estimate the risk of cancer to a carrier with a mutated BRCA1 gene. See, e.g., “Breast and Ovarian Cancer Incidence in BRCA I –Mutation Carriers”, Douglas F. Easton, Deborah Ford, D. Timothy Bishop, and the Breast Cancer Linkage Consortium, Am. J. Hum. Genet. 56:265-271, (1995). More specifically, the authors of this study were able to show the cumulative risk of breast cancer for carriers of the BRCA1 mutation was 85% by the age of 70.

Of those women with BRCA1-related cancer, approximately 80%-90% are ER, PR and HER2 negative (so-called triple-negative). See, e.g.: “Prevalence of BRCA1 mutations in triple negative breast cancer (BC)”, M. J. Kandel, Z. Stadler, S. Masciari, L. Collins, S. Schnitt, L. Harris, A. Miron, A. Richardson and J. E. Garber, Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 24, No 18S (June 20 Supplement), 2006: 508.

However, only about 15% of triple-negative breast cancer victims are BRCA1-related. For a recent study addressing this issue, see: Fostira F, Tsitlaidou M, Papadimitriou C, et al., “Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study”, Breast Cancer Research and Treatment 2012 (published online before print Mar 21 2012).

BRCA1, triple-negative breast cancer and non-BRCA1, triple-negative breast cancer have different causes. For example, the breast cancer gene BRCA1 leaves breast cells vulnerable to cancer by reducing their ability to repair DNA damage, causing genetic instability. See, for example, “BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair”, PJ O’Donovan, Carcinogenesis, Volume 31, Issue 6, p. 961-967 (2010). This is not the case with non-BRCA1, triple-negative cancer victims.

Similarly, BRCA1-related cancers demonstrate different responses to chemicals than that observed with other cancers given the unique causative effect of the mutated gene. See, for example, “Targeted Chemotherapy? Platinum in BRCA1-Dysfunctional Breast Cancer”, Lisa Carey, © 2009 by American Society of Clinical Oncology.

Given the differences between BRCA1 and non-BRAC1 cancer patients, the results of any clinical trial of the overall group of triple-negative patients cannot be applied with statistical validity to the BRCA 1 sub-category of triple-negative patients unless that sub-category is specifically separated out and monitored.

For a generic explanation of the statistical considerations in trials, see “Clinical Trials: Statistical Considerations” by Theresa A Scott, MS, Vanderbilt University, Department of Biostatistics, http://biostat.mc.vanderbilt.edu/TheresaScott (particularly pages 41-44).

A simple example may help illuminate this point. Let’s consider a trial of 100 triple-negative patients, of which 15 patients are BRCA1. Let’s say that chemical X was administered to the group, and that the 85 non-BRCA1 patients showed an average life expectancy of 7 years, or two years more than that from treatment with chemical Y. On the other hand, let’s say that the 15 BRCA1 participants experienced an average life expectancy of 3 years after the application of chemical X. If the subgroup of BRCA1 patients were not separated out, the average life expectancy of all triple negative patients in the trial would be reported as 6.4 years, or 1.4 years longer than with the use of chemical Y. The results would suggest the use of chemical X over Y for triple-negative patients, but that would be a deadly prescription for the subgroup of BRCA1 patients.

This sampling bias can happen in the opposite direction as well. That is, a benefit to BRCA1 triple-negative patients can be masked by a lack of benefit to non-BRCA1, triple-negative patients if the two subgroups are not tracked separately.

There is little research that separates out the effects of ACT on BRCA1, triple-negative patients versus non-BRCA1, triple-negative patients.

Despite the paucity of segmented statistical analysis, the National Cancer Institute website says: “BRCA1 mutation carriers who do not receive chemotherapy may have a worse prognosis”. It goes on to say that: “because most BRCA1-associated breast cancers are triple negative, they are usually treated with adjuvant chemotherapy”. See: http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional/page4#Section_2056.

The NCI cites only one study for the above proposition. That study states that: “A retrospective cohort study of 496 Ashkenazi Jewish (AJ) breast cancer patients from two centers compared the relative survival among 56 BRCA1/BRCA2 mutation carriers followed for a median of 116 months. BRCA1 mutations were independently associated with worse disease-specific survival. The poorer prognosis was not observed in women who received chemotherapy”, Robson ME, Chappuis PO, Satagopan J, et al., “A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment”, Breast Cancer Res 6 (1): R8-R17, 2004.

However, the study also says:

“Adjuvant treatment was not randomly assigned, and therefore the association between administration of chemotherapy and a poor outcome (P < 0.0001) is probably accounted for by the fact that women who were given chemotherapy had a higher a priori probability of death than did those not receiving adjuvant chemotherapy. For this reason, use of chemotherapy was not included as a variable in the final multivariate model.”

Presumably because the use of chemotherapy was not included in the final model, the authors do not provide the estimates of mortality for BRCA1 patients with and without adjuvant chemotherapy. However, the authors report:

“In univariate analysis the presence of a germline BRCA1 mutation was significantly associated with a worse breast cancer specific survival both among those women who received chemotherapy (10-year breast cancer mortality 41% in carriers versus 24% in noncarriers; P = 0.04) and among those who did not (10-year breast cancer mortality 24% in carriers versus 9.6% in noncarriers; P = 0.008).”

Given that the authors specify in Table 1 that 24 BRCA1 patients received chemotherapy and 17 did not, the above quote implies that 10 of 24 patients who received chemotherapy died in the study period and that 4 of 17 who did not receive chemotherapy had died. Hence, the raw data supports the exact opposite of the conclusion of that stated on the NCI website. That is, adjuvant chemotherapy (typically ACT) of BRCA1 patients was associated with a greater incidence of death.

It is important to note that two of the three drugs in the ACT chemotherapy regime cause DNA damage.

Adriamycin both blocks DNA production in cells, and also inhibits the enzymes responsible for repairing DNA. Cells can’t live without DNA; thus when they’re deprived of it, they die (in fact, some even kill themselves when their DNA is damaged). Adriamycin can’t distinguish between cancer cells and normal cells; but because cancer cells are dividing so rapidly, it has a greater negative effect on cancer cells than on normally dividing cells. In turn, Cytoxan stops cancer cells from replicating. And Taxol slows or stops cell division, or keeps enzymes from making the proteins cells need in order to grow. Working in combination, ACT consists of powerful agents working to destroy fast growing cells such as cancer.

The hallmark of BRCA1 carriers is that they do not have the ability to repair double-strand DNA breaks, which can lead to the formation of cancerous tumors. For example, a team of scientists at Johns Hopkins University ran tests on the two cell types – the ones that had the BRCA1 mutation, and the original cells that had two healthy copies of BRCA1 – and compared their DNA repair activity. They were able to show that cells with BRCA1 mutations were less efficient at conducting the type of DNA repair known to involve the BRCA1 protein. The BRCA1-mutated cells were more likely to die when exposed to a DNA-damaging chemotherapy drug or radiation. BRCA1-mutated cells allowed to divide for several weeks also were more likely to lose other genes, including genes often mutated in breast tumors. Tests on non-cancerous breast cells taken from women with BRCA1 mutations showed similar genetic losses.

See: “Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells”, Hiroyuki Konishi, Morassa Mohsenia, Akina Tamakia, Joseph P. Garaya, Sarah Croessmanna, Sivasundaram Karnanb, Akinobu Otab, Hong Yuen Wonga, Yuko Konishia,b, Bedri Karakasa, Khola Tahirc, Abde M. Abukhdeira, John P. Gustina, Justin Cidadoa, Grace M. Wanga, David Cosgrovea, Rory Cochrana, Danijela Jelovaca, Michaela J. Higginsa, Sabrina Arenaa,2, Lauren Hawkinsa, Josh Lauringa, Amy L. Grossa, Christopher M. Heaphya, Yositaka Hosokawab, Edward Gabrielsona, Alan K. Meekera, Kala Visvanathana, Pedram Argania, Kurtis E. Bachmanc, and Ben Ho Parka, Proceedings of the National Academy of Sciences of the United States of America, Published online before print October 10, 2011.

Taken together, there is reason to believe that the use of ACT has an adjunctive therapy for BRCA1 patients may be creating disproportionate deleterious side effects for this group. An analogous situation came to light recently with the realization that increased radiation from mammograms for BRCA1 carriers under the age of 30 was causing more harm than good. See “Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study”, Nadine Andrieu, et al., BMJ 2012; 345:e5660.

Finally, there are better alternatives available for BRCA1 breast cancer patients seeking adjuvant therapy than ACT.

For example, a recent study showed that BRCA1 PM methylation was detected in approximately 30% of TNBC patients and was associated with significantly poor outcomes using standard anthracycline chemotherapy. The authors conclude that: “Alternative therapeutic modalities (platinum/PARP inhibitors) which are more likely to be effective against BRCA1-deficient tumors should be explored for patients with sporadic TNBC and BRCA1 PM.” See “Association of BRCA1 promoter methylation in triple-negative breast cancer (TNBC) with resistance to standard anthracyline-based adjuvant chemotherapy”, P. Sharma, B. F. Kimler, Y. A. Park, S. R. Stecklein, Q. J. Khan, B. K. Petroff, O. W. Tawfik, R. A. Jensen; University of Kansas Cancer Center Medical Center, Westwood, KS; University of Kansas Medical Center, Westwood, KS; University of Kansas Medical Center, Kansas City, KS; University of Kansas Cancer Center, Kansas City, KSJ Clin Oncol 29: 2011 (suppl; abstr 1123).

See also: “Oncology Pathologic Complete Response Rates in Young Women With BRCA1-Positive Breast Cancers After Neoadjuvant Chemotherapy”, Tomasz Byrski, Jacek Gronwald, Tomasz Huzarski, Ewa Grzybowska, Magdalena Budryk, Malgorzata Stawicka, Tomasz Mierzwa, Marek Szwiec, Rafal Wiśniowski, Monika Siolek, Rebecca Dent, Jan Lubinski and Steven Narod, © 2009 by American Society of Clinical.

On an overall basis, there is a sufficient basis for the FDA to modify the industry-wide practice of administering ACT chemotherapy to BRCA1 triple-negative breast cancer victims because: a) there is little to no factual evidence to support its purported efficacy in the subgroup; 2) there is reason to believe that it is disproportionately harmful to this subgroup of patients and 3) there are alternatives readily available for this subgroup with better results in clinical trials.

Legal Basis for Requested Relief

The statutory purpose of the Food and Drug Administration (FDA) is to protect public health by ensuring that products under its domain are safe and effective for human use.

As documented herein, BRCA1, triple-negative breast cancer is a distinct sub-group of triple-negative cancer and should be treated as a separate category of breast cancer.

An ACT-based chemotherapy regimen consists of cytotoxic drugs that are used to kill and/or prevent the growth of cancer cells. The perceived benefits of ACT to the BRCA1 subgroup of triple-negative patients are largely unproven and do not necessarily flow from the benefits of ACT upon the broader group of triple-negative patients.

These chemicals also cause hair loss, nausea, and pain among many other unpleasant side effects, including increased emotional stress. These effects may be compounded for BRCA1 patients given the diminished ability of these patients to repair damaged DNA.

In other words, an assessment of the risks and benefits of ACT as an adjuvant therapy for the subgroup of BRCA1, triple-negative patients is not likely to pass regulatory scrutiny.

Given these factors, the FDA should recognize BRCA1 breast cancer as a distinct cancer group and withdraw approval of ACT chemotherapy to treat BRCA1, triple-negative breast cancer patients.

Other Related Issues

The state of computer technology and networking is such that it is providing an expanding opportunity to move from an environment with a few types of identifiable cancer to one with many identifiable types of cancer. For example, a genetics company named 23andme.com has opened its application programming interface to third party developers to enable data mining of the company’s data sets. See: https://www.23andme.com/about/press/open_api/. Such an approach as well as others being developed holds the promise to improve the efficacy of treatments for each new type of cancer and possibly for each newly diagnosed patient. However, the mainstream medical profession and the FDA’s processes are not prepared to deal with this new reality.

The research around BRCA1 provides a good illustration of the current process. For example, several years ago, scientists announced that: “Our study indicates that a high proportion of women with BRCA1-associated breast cancers will respond to platinum-based chemotherapy.” See: “Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients”, T. Byrski, T. Huzarski, R. Dent, J. Gronwald, D. Zuziak, C. Cybulski, J. Kladny, B. Gorski, J. Lubinski and S. A. Narod, Breast Cancer Research and Treatment, Volume 115, Number 2 (2009), 359-363, DOI: 10.1007/s10549-008-0128-9.

While these results have been categorized as “impressive” and “thought-provoking” by the scientific community, progress has been very slow on pursuing platinum-based chemotherapy for BRCA1 patients under the FDA’s existing processes. That said, other studies have duplicated the above results, and the results are better than the alternative of applying ACT to BRCA1 patients. Nevertheless, without an out-of-the-ordinary measure taken by the FDA as requested in this Petition, BRCA1 patients will continue to be subjected to ACT chemotherapy for years to come.

In a separate line of research addressing BRCA1 breast cancer, similarly impressive results were achieved in Phase 2 trials of PARP inhibitors. See, e.g., “Phase II trial of the oral PARP inhibitor Olaparib in BRCA-deficient advanced breast cancer”, A. Tutt, M. Robson, J. E. Garber, S. Domchek, M. W. Audeh, J. N. Weitzel, M. Friedlander, J. Carmichael; Breakthrough Breast Cancer Research Unit, Kings College London School of Medicine, Guy’s Hospital, London, United Kingdom; Memorial Sloan-Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; University of Pennsylvania, Philadelphia, PA; Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA; City of Hope Comprehensive Cancer Center, Duarte, CA; Prince of Wales Cancer Centre, Sydney, Australia; AstraZeneca, Macclesfield, United Kingdom, J Clin Oncol 27:18s, 2009 (suppl; abstr CRA501).

Despite this initial success, the progress on PARP inhibitors recently came to a crashing halt with the announcement of the “failure” of the Phase 3 results of Iniparib. See, e.g., O’Shaughnessy J, Schwartzberg LS, Danso MA et al. “A randomized phase III study of Iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC)”, presented at the 2011 annual meeting of the American Society of Clinical Oncology. Chicago, IL. June 3-7, 2011.

The construct of this Phase 3 trial and the real-world result raises a troubling concern because PARP inhibitors are targeted to work with BRCA1 patients, but the study’s design addressed the broad category of triple-negative patients and apparently did not track the results for the sub-group of BRCA1 carriers. As discussed in the body of this Petition, this construct fails the laws of statistical analyses.

For example, as Doctors Jorge Rios and Shannon Puhalla of the University of Pittsburg Cancer Institute explain: “In a population of TNBC patients, in which some patients would be BRCA1/2-positive, there is also the potential for disparate numbers of mutation carriers in the phase II and phase III studies, which could affect the results”. See: “PARP Inhibitors in Breast Cancer: BRCA and Beyond”, Oncology (Williston Park) 2011 Oct; 25(11):1014-25.

Given the harm that this study has caused this group of patients through further delays, the FDA should issue a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) Letter to the principle investigator of this Phase 3 trial to gather additional information.

Unfortunately, the FDA’s current processes and practices are not prepared to capitalize on the newly emerging research from improved technology, nor is it generally prepared to police the potential delaying tactics of the incumbent drug manufacturers.

Nevertheless, as a first step, this Petition provides an opportunity for the FDA to recognize a distinct subgroup of cancer patients and thereby improve medical care for up to 15,000 women every year by applying the current state of scientific knowledge to this group of patients on an expedited basis.

Certification

The undersigned certifies, that, to his best knowledge and belief, this Petition includes all information and views on which the Petition relies, and that it includes representative data and information known to the petitioner that are unfavorable to the petition.

By: _____________________________

Steven A. Zecola