“Triple-negative breast cancer is particularly troubling to all of us. I hope the science we’re undertaking will ultimately lead to the opportunity to tailor our selection of cytotoxic agents more carefully….”

— Nancy Davidson, MD

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WITHIN THE SPECTRUM of breast cancer subtypes, triple-negative disease is “particularly troubling,” but better scientific understanding of this malignancy is leading to advances in its treatment, according to breast cancer expert Nancy Davidson, MD. 

Triple-negative breast cancer does not express the estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 (HER2). This particular subtype is especially common in BRCA1-mutation carriers (over 80%) and is overrepresented in premenopausal and African women. About 15% to 20% of breast cancers are triple-negative. 

“Our understanding has been greatly increased over the past several years, and our clinical and translational research has been driven by a seminal paper¹ that suggested there are distinct subtypes within the subtype of triple-negative breast cancer,” said Dr. Davidson, who is Immediate Past President of the American Association for Cancer Research (AACR), Executive Director of the Fred Hutchinson Cancer Research Center and the Seattle Cancer Care Alliance, and Head of Medical Oncology at the University of Washington School of Medicine. 

At the AACR International Conference on New Frontiers in Cancer Research in Cape Town, South Africa, Dr. Davidson reviewed key data in the treatment of four of the six subtypes of triple-negative breast cancer identified by gene-expression array: the basal-like 1 and 2 subtypes, the immunomodulatory subtype, and the luminal androgen receptor subtype. 

Basal-Like 1 and 2 Subtypes 

ONE LARGE TRIAL in the United States (Cancer and Leukemia Group B 40603 [Alliance]) examined the effect of preoperative carboplatin and the angiogenesis inhibitor bevacizumab (Avastin) in triple-negative breast cancer.² In this trial, the addition of bevacizumab significantly increased pathologic complete response in the breast, but not in the axillae. It also resulted in more side effects. 

“At the end of the day, it was decided that the use of this agent wasn’t really appropriate in the context of this multimodal chemotherapy,” said Dr. Davidson. “As a consequence of this trial and others, bevacizumab has fallen off the radar as a form of treatment for breast cancer of any stage.” 

But the addition of carboplatin was more promising, she noted. Carboplatin increased pathologic complete response in the breast and the axillae, with side effects typically expected from chemotherapy. “This trial brought out the possibility that we should be thinking about platinums more actively in the context of managing this particular type of breast cancer,” she said. 

Taxanes are also active agents in breast cancer. In the phase III trial of carboplatin vs docetaxel in triple-negative or BRCA1/2-positive metastatic breast cancer (TNT trial),³ germline BRCA-mutation carriers had a much better response rate to carboplatin than docetaxel, but lacking a germline mutation, carboplatin and docetaxel were equally effective. This trial was important because it looked at clinical outcomes in the context of the BRCA germline status, the homologous recombination deficiency assay, BRCA1 methylation status, and BRCA1 mRNA silencing. “It’s pretty clear that in this study, germline BRCA mutation status was very important in determining response to chemotherapy,” Dr. Davidson said. 

Also in this trial, the homologous recombination deficiency assay for “BRCA-ness,” or biology that might be similar to a BRCA mutation, was not useful in differentiating responses to either agent. The response to the chemotherapy agents seems to vary depending on how the BRCA gene is inactivated. “So if inactivation is because of BRCA methylation, you get one result, but if it’s because of silencing, you get another result,” she explained. “What I take away from this is that the means by which these genes are inactivated are obviously biologically different and might also have meaningful clinical implications.” 

In the phase II TBCRC009 trial of cisplatin or carboplatin in metastatic triple-negative breast cancer,⁴ the overall response rate in 86 patients was 25.6%, but it was higher for cisplatin (32.6%) and particularly high for those with BRCA1/2 mutations (54.5%). “This body of data suggests that platinums really are active agents in this subtype of breast cancer,” said Dr. Davidson. 

DNA repair pathways are also important targets for therapy in this setting. BRCA1/2 and “BRCA-like” triple-negative breast cancer can be vulnerable to poly ADP-ribose polymerase (PARP) inhibition. “PARP is a reasonable target for therapy in a variety of settings, including here,” she said. In the United States, two PARP inhibitors, olaparib (Lynparza) and rucaparib (Rubraca), are currently approved for the treatment of BRCA1/2-positive ovarian cancers. (Another PARP inhibitor, niraparib [Zejula], is approved for the treatment of recurrent ovarian cancer regardless of BRCA status.) 

One early-phase study⁵ was an attempt to determine whether PARP inhibitors should be taken forward in more advanced clinical trials. The addition of the PARP inhibitor veliparib to carboplatin, with or without paclitaxel, resulted in higher rates of pathologic complete response than standard therapy alone, specifically in triple-negative breast cancer. “This trial allows us to credential a combination worthy of study in a larger clinical trial,” said Dr. Davidson. 

In the phase II BROCADE study of paclitaxel/carboplatin with or without veliparib in BRCA1/2-positive metastatic breast cancer,⁶ the addition of veliparib showed a trend toward improvement in disease-free survival and overall survival. “It’s pretty clear that the chemotherapy matters. When we used the same veliparib but with temozolomide, the results were inferior to the arms that included carboplatin and paclitaxel,” she explained. “This allows us to think more about the specific chemotherapy as well as the role of the PARP inhibitor in the setting of this particular subset of breast cancer.” 

“We’re now in a position where we can think about bringing these PARP inhibitors into the earliest stages of breast cancer,” she added. An ongoing international trial is evaluating the use of olaparib in the adjuvant setting in patients with BRCA-positive breast cancer (ClinicalTrials.gov identifier NCT02032823). 

Immunomodulatory and Luminal Androgen Receptor Subtypes 

THERE IS CURRENTLY enormous interest in immunotherapy, and about 60% of metastatic triple-negative breast cancers express the programmed cell death ligand 1 (PD-L1). In the phase Ib KEYNOTE-012 trial of the anti–programmed cell death protein 1 (PD-1) agent pembrolizumab (Keytruda),⁷ about 58% of advanced triple-negative breast cancer patients expressed PD-L1, and their response rate approached 20%. 

“These results suggest this might be a fertile territory for applying checkpoint inhibitors,” said Dr. Davidson. That work is being taken forward in an ongoing randomized phase III study of pembrolizumab in triple-negative breast cancer patients with residual disease after preoperative chemotherapy, to evaluate the benefit of adjuvant pembrolizumab in reducing recurrence (ClinicalTrials.gov identifier: NCT02954874). 

In a pivotal phase II study of the androgen receptor inhibitor enzalutamide (Xtandi) in advanced androgen receptor–positive triple-negative breast cancer (MDV3100-11 trial),⁸ 80% of triple-negative breast cancer patients demonstrated some level of androgen receptor expression. Clinical benefit in the subset with the highest expression was 30% at 6 months, suggesting activity of antiandrogens in triple-negative breast cancer. 

“Triple-negative breast cancer is particularly troubling to all of us,” Dr. Davidson added. “I hope the science we’re undertaking will ultimately lead to the opportunity to tailor our selection of cytotoxic agents more carefully and also to appropriately use targeted agents in the patients most likely to benefit.” ■

DISCLOSURE: Dr. Davidson reported no conflicts of interest. 

REFERENCES 

1. Lehmann BD, Bauer JA, Chen X, et al: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750-2767, 2011. 

2. Sikov WM, Berry DA, Perou CM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant weekly paclitaxel followed by dose-dense AC on pathologic complete response rates in triple-negative breast cancer. J Clin Oncol 33:13-21, 2015. 

3. Tutt A, Ellis P, Kilburn L, et al: BRCA1 methylation status, silencing and treatment in the TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer. 2016 San Antonio Breast Cancer Symposium. Abstract S6-01. 

4. Isakoff SJ, Mayer EL, He L, et al: TBCRC009: A multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J Clin Oncol 33:1902-1909, 2015.

5. Rugo HS, Olopade OI, DeMichele A, et al: Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 375:23-34, 2016. 

6. Han HS, Diéras V, Robson ME, et al: Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study. 2016 San Antonio Breast Cancer Symposium. Abstract S2-05. 

7. Nanda R, Chow LQ, Dees EC, et al: Pembrolizumab in patients with advanced triple-negative breast cancer: Phase Ib KEYNOTE-012 study. J Clin Oncol 34:2460-2467, 2016. 

8. Traina TA, Miller K, Yardley DA, et al: Results from a phase 2 study of enzalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer. 2015 ASCO Annual Meeting. Abstract 1003. Presented June 1, 2015.