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Treatment of Triple-Negative Breast Cancer With BRCA1/2 Mutations: More to Learn From Ongoing Trials


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The treatment of triple-negative breast cancer remains a clinical challenge with no single validated target, though numerous pathways are druggable and are being investigated. In the subset of BRCA-mutated triple-negative breast cancer, the approval of the first poly (ADP-ribose) polymerase (PARP) inhibitor for metastatic breast cancer expanded the treatment options beyond traditional chemotherapy agents. With that said, there is evidence that certain chemotherapy agents such as the platinum compounds may be associated with greater antitumor activity than other commonly used agents such as docetaxel in the subset of patients with BRCA-mutated tumors.

TNT —triple-negative trial—was a large, randomized phase III trial in advanced triple-negative breast cancer or BRCA1/2-associated breast cancer of any receptor status seeking to test the hypotheses of differential platinum sensitivity in biologic subgroups of triple-negative breast cancer.1 Prespecified subgroup analyses tested this hypothesis in those with a germline BRCA mutation, mutational signatures of hormone receptor deficiency, or methylation of BRCA1 causing epigenetic silencing of BRCA1 mRNA. Patients were randomized to receive carboplatin or docetaxel and on progression of disease were allowed to cross over to the other agent if clinically appropriate.

In patients with a germline BRCA1/2 mutation, the objective response rate to carboplatin was 68%, compared with 33% in those receiving docetaxel, although there was no statistical difference in objective response rate between carboplatin and docetaxel in those without a germline BRCA1/2 mutation. Similarly, progression-free survival was numerically improved with carboplatin (6.8 months) vs docetaxel (4.4 months) in those with a BRCA1/2 mutation, but this effect was absent in those lacking a mutation.

Pathologic Complete Response: Discordant Study Results

In the neoadjuvant setting, the translation of improved pathologic complete response into improvement in disease-free or overall survival has not always been consistent.2 Previous reports have suggested that those patients with triple-negative breast cancer who attain a pathologic complete response tend to do well over the long term compared with their counterparts with less than a pathologic complete response at surgery (eg, residual disease). In the latter group, the risk of death is much higher. In clinical trials of patients with axillary node-positive or high-risk node-negative disease treated with preoperative chemotherapy, with or without a platinum, discordant results have been reported.


It remains difficult to see unifying and consistent data that support [platinum agents or bevacizumab] as ‘must-use’ or standard-of-care regimens for all patients with triple-negative breast cancer.
— William J. Gradishar, MD, FASCO, FACP

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In CALGB 40603, patients with early-stage triple-negative breast cancer were randomized in a 2 2 design to receive weekly paclitaxel followed by dose-dense doxorubicin plus cyclophosphamide (AC) alone, with concurrent bevacizumab (Avastin), with carboplatin during weekly paclitaxel, or the combination of bevacizumab with carboplatin and standard chemotherapy.3 The pathologic complete response rate in the breast/axilla was higher with the addition of carboplatin (54% vs 41%), but the regimen was associated with markedly higher toxicity. The addition of bevacizumab did not improve pathologic complete response in the breast/axilla. Patients assigned to receive carboplatin vs not had a 3-year event-free survival of 76.5% vs 71.6%. Patients assigned to receive bevacizumab vs not had a 3-year event-free survival of 75.5% vs 72.9%. This study demonstrated that those patients achieving a pathologic complete response had a better outcome, but it was not powered to assess the impact of carboplatin and bevacizumab on event-free or overall survival.

In the phase II GeparSixto trial, patients with stage II/III triple-negative breast cancer were randomized to receive preoperative weekly paclitaxel, nonpegylated liposomal doxorubicin, and bevacizumab, with or without weekly carboplatin.4 In those patients receiving carboplatin, the pathologic complete response rate was 53.2%, compared with 36.9% in those not receiving carboplatin (P = .005). Interestingly, the effect of adding carboplatin was most pronounced in those with wild-type BRCA compared with those with a germline mutation in BRCA. The disease-free survival was greater for those receiving carboplatin than for those who did not receive carboplatin (85.8% vs 76.1%).

The discordant results between these two trials may have to do with what some consider suboptimal chemotherapy in GeparSixto as well as the different schedules of drug administration potentially resulting in different drug exposure.

Potential Role of Bevacizumab

Now, the results of the GeparQuinto study—reviewed in this issue of The ASCO Post—offer more insights into the possible role of bevacizumab in triple-negative breast cancer.5 The trial recruited both HER2-positive and HER2-negative patients, but the 1,948 patients with HER2-negative disease were randomized to receive epirubicin/cyclophosphamide (4 cycles) followed by docetaxel (4 cycles), with or without bevacizumab, from the outset of preoperative chemotherapy until surgery. Of those with HER2-negative disease, 663 patients had triple-negative breast cancer, and 90 of the 1,948 patients were determined to have germline BRCA1/2 mutations. In the germline mutation group, 49% received bevacizumab and 57% received chemotherapy alone.

Interestingly, the patients with BRCA1/2 mutations had higher pathologic complete response rates as a whole than did those patients with triple-negative breast cancer who did not have a germline mutation, and those with a germline mutation receiving bevacizumab had a higher pathologic complete response than did those without a germline mutation. The improvement in pathologic complete response rate in those with a germline mutation did not improve disease-free survival, whereas in those lacking a germline mutation, an increased pathologic complete response was associated with improved disease-free survival.

More Answers Needed

Although these trials offer potential signals suggesting the benefit of platinum agents or bevacizumab in patients with triple-negative breast cancer, it remains difficult to see unifying and consistent data that support these agents as “must-use” or standard-of-care regimens for all patients with triple-negative breast cancer. Dissecting the subset of patients who benefit, determining the optimal regimen to partner with these agents, and understanding the underlying molecular mechanism that may explain their effect are the focus of ongoing preclinical and clinical work.

In the ongoing NRG-BR003 trial, patients with early-stage triple-negative breast cancer are randomized to receive AC 4 followed by weekly paclitaxel or the same chemotherapy with carboplatin beginning with paclitaxel. This trial and others will hopefully identify a new standard of care for triple-negative breast cancer and those who have germline BRCA1/2 mutations. ■

Dr. Gradishar is Chief, Division of Hematology/Oncology; Director, Maggie Daley Center for Women’s Cancer Care; Deputy Director, Clinical Network, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University Feinberg School of Medicine, Chicago.

DISCLOSURE: Dr. Gradishar reported no conflicts of interest.

REFERENCES

1. Tutt A, et al: Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT Trial. Nature Med 24:628-637, 2018.

2. Liedtke C, et al: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26:1275-1281, 2008.

3. Sikov WM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33:13-21, 2015.

4. von Minckwitz G, et al: Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): A randomised phase 2 trial. Lancet Oncol 15:747-756, 2014.

5. Fasching PA, et al: BRCA1/2 mutations and bevacizumab in the neoadjuvant treatment of breast cancer: Response and prognosis results in patients with triple-negative breast cancer from the GeparQuinto study. J Clin Oncol 36:2281-2287, 2018.


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