Steven E. Vogl, MD
At the 2019 San Antonio Breast Cancer Symposium, Nadine Tung, MD, of Beth Israel Deaconess Medical Center, presented a multisite study called INFORM, run by the Translational Breast Cancer Research Consortium.1 It compared single-agent cisplatin with a “classic” combination of doxorubicin and cyclophosphamide (AC) as preoperative chemotherapy in women carrying deleterious BRCA1 and BRCA2 mutations. Cisplatin was no better, and numerically worse, in inducing pathologic complete remission than was AC. The pathologic complete remission rate was 18% for cisplatin and 26% for AC. For those with triple-negative cancers (mostly BRCA1-mutation carriers), the pathologic complete remission rates were 22% for cisplatin and 28% for AC. Rates of pathologic complete remission were just slightly lower for carriers of BRCA2 than for BRCA1.
Before this presentation, mutation-associated breast cancer was reported to have a 60% pathologic complete remission rate to single-agent cisplatin based on 12 patients culled from a large retrospective registry study with BRCA1 mutations in Poland.2 A second study, also from Poland, confirmed a 61% pathologic complete remission rate in BRCA1 carriers with breast cancer among 107 women enrolled in a phase II trial between 2006 and 2014.3 The pathologic complete remission rate for AC was reported at about 20% for AC in other trials. Dr. Judith Garber, the senior author of the INFORM study, had reported two of two pathologic complete remission among mutation carriers in a phase II trial of neoadjuvant cisplatin in women with triple-negative breast cancer.
The Importance of Trials Like INFORM
The conclusion was that cisplatin does not work much worse than other chemotherapy for induction therapy of breast cancers in mutation carriers, but it does not work better, either. This conclusion does not get headlines. It does not report a major advance that lengthens life or improves its quality. There is no great leap forward. Yet, trials like this are very important! They remove errors from the oncology literature and allow physicians to avoid giving the wrong treatment to patients for whose care they are responsible.
The metaphor from the title of this commentary is the pruning of dead branches. If the branches are left, then oncologists and their patients will climb onto them, and some of the patients will be hurt in “falls” when the branches break (less efficacy and increased renal and neurologic toxicities). Extending the metaphor, injuries from falling dead branches can cause harm even if no one is climbing on them. Erroneous conclusions can inhibit research on improved therapies because they misdirect the design of new therapies. We physicians and our patients should all be grateful for the conduct and reporting of this trial, even though it could not achieve its target accrual in a reasonable period.
INFORM should take its place among negative randomized breast cancer trials that failed to confirm previously encouraging phase II data. Among the most important was the ECOG study of high-dose chemotherapy and autologous stem rescue for metastatic breast cancer.4 Were it not for a randomized trial led by MD Anderson,5 we would still be giving 96-hour infusions of paclitaxel, based on a suggestion from Memorial Sloan Kettering that prolonged infusions were effective in 7 of 26 patients when prior short infusions of paclitaxel or docetaxel had failed to control metastatic breast cancer.6 Were it not for a subsequent negative phase III trial,7 we would all be giving iniparib with gemcitabine and carboplatin as the chemotherapy of choice for metastatic triple-negative breast cancer, based on a moderate-sized randomized phase II trial.8
If -Richard Fisher and the SWOG had not done a four-arm randomized trial in diffuse large B-cell lymphoma of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) vs “newer, more active, second-, and third-generation” combination chemotherapy regimens, we would not know that, even though they belonged to successive generations of higher ordinal number, outcomes were superimposable!9 Similarly, were it not for a recent CALGB study, we could not confidently continue to give standard rituximab (R)-CHOP to patients with disseminated diffuse large B-cell lymphoma rather than a promising infusional regimen (dose-adjusted R-EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin]) that was both more complicated and more toxic, but no more effective.10
New Situation: Neoadjuvant PARP Inhibitors
We currently have a new situation regarding neoadjuvant PARP (poly [ADP-ribose] polymerase) inhibitors in a BRCA1- and BRCA2-mutated breast cancer population, similar to that studied by INFORM. Talazoparib, an oral PARP inhibitor, given for 6 months as preoperative induction therapy in a nonrandomized trial of 20 women with BRCA mutations, was reported at a 2019 ASCO plenary session as inducing a pathologic complete remission rate of 53%.11 Whether pathologic complete remission from a PARP inhibitor has a similar effect on preventing relapse and prolonging life as a pathologic complete remission to chemotherapy remains unknown. Hopefully, we will someday have the results of a phase III randomized trial to define both the value of achieving pathologic complete remission with a PARP inhibitor and whether a PARP inhibitor should be given instead of, or together with, systemic neoadjuvant chemotherapy before surgery in BRCA-mutation carriers.
If this study is ever completed, we should be as grateful at the time of its reporting as I am now to Dr. Tung and the Translational Breast Cancer Research Consortium for completing and reporting the -INFORM study. Without properly done and analyzed trials like this, our patients would suffer grievously.
DISCLOSURE: Dr. Vogl reported no conflicts of interest.
REFERENCES
1. Tung N, Arun B, Hofstatter E, et al: Cisplatin versus doxorubicin/cyclophosphamide as neoadjuvant treatment in germline BRCA mutation carriers with HER2-negative breast cancer: Results from the INFORM trial (TBCRC 031). 2019 San Antonio Breast Cancer Symposium. Abstract GS6-03. Presented December 13, 2019.
2. Byrski T, Gronwald J, Huzarski T, et al: Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 28:375-379, 2010.
3. Byrski T, Huzarski T, Dent R, et al: Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 147:401-405, 2014.
4. Stadtmauer EA, O’Neill A, Goldstein LJ, et al: Conventional-
dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer: Philadelphia bone marrow transplant group. N Engl J Med 342:1069-1076, 2000.
5. Moulder SL, Holmes FA, Tolcher AW, et al: A randomized phase II trial comparing 3-hour vs 96-hour infusion schedules of paclitaxel for the treatment of metastatic breast cancer. Cancer 116:814-821, 2010.
6. Seidman AD, Hochhauser D, Gollub M, et al: Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. J Clin Oncol 14:1877-1884, 1996.
7. O’Shaughnessy J, Schwartzberg L, Danso MA, et al: Phase III study of iniparib plus gemcitabine and carboplatin vs gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol 32:3840-3847, 2014.
8. O’Shaughnessy J, Osborne C, Pippen JE, et al: Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364:205-214, 2011.
9. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993.
10. Bartlett NL, Wilson WH, Jung S-H, et al: Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: Clinical outcomes of the phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol 37:1790-1799, 2019.
11. Litton JK, Scoggins ME, Hess KR, et al: Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J Clin Oncol. August 28, 2019 (early release online).
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
