Tackling the Heterogeneity of Triple-Negative Breast Cancer

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Mohammad Jahanzeb, MD

We now accept the heterogeneity of [triple-negative breast cancer], and it’s natural that we think of these groups differently in terms of treatment.

—Mohammad Jahanzeb, MD

Triple-negative breast cancer is now recognized as a very complex subtype for which one treatment will not be applicable to all, according to Mohammad Jahanzeb, MD, Professor of Clinical Medicine at the University of Miami and Director of the UM Sylvester Deerfield Campus, who gave an update on this challenging tumor at the 9th Annual New Orleans Summer Cancer Meeting.

Triple-negative breast cancer gene-expression subtypes are associated with distinct molecular features. The vast majority are basal-like, but in a recent study that applied the PAM50 signature to the triple-negative intrinsic subtypes, there was no uniform distribution of the basal-like signature.1 This suggests that there are distinctly different groups within triple-negative breast cancer that may respond to different therapies.

“It supports the notion that [triple-negative breast cancer] is not a uniform group of patients,” he said.

In another recent study, Masuda et al2 showed that triple-negative breast cancer subtype was an independent predictor of pathologic complete response to neoadjuvant chemotherapy (P = .022), again suggesting that patients may respond differently to the same neoadjuvant regimen. Within the basal-like-1 subtype, a pathologic complete response was achieved by 52%, compared to just 10% within the luminal androgen receptor subtype.

Finding the Right Treatment

“We now accept the heterogeneity of [triple-negative breast cancer], and it’s natural that we think of these groups differently in terms of treatment,” Dr. Jahanzeb said. “Maybe for BRCA-mutated patients we will treat with a platinum, [poly(ADP-ribose) polymerase] (PARP) inhibitor, or stem cell inhibitor, while using androgen blockade for the luminal androgen receptor group, and epidermal growth factor inhibitors or immune therapies for other histologic types,” he added.

“There is not a single approved treatment restricted to [triple-negative breast cancer], and no guidelines that direct us to a gold standard,” he noted.

Triple-negative breast cancer patients can be highly sensitive to cytotoxic chemotherapy with numerous agents, though some surprises do occur, he said. At the ASCO Annual Meeting 2 years ago, Rugo et al reported disappointing results from Cancer and Leukemia Group B (CALGB) 40502, which compared nab-paclitaxel ­(Abraxane)/bevacizumab (Avastin), paclitaxel/bevacizumab, and ixabepilone (Ixempra)/bevacizumab.3 The nab-paclitaxel and paclitaxel arms produced comparable results, while ixabepilone proved inferior.

In an earlier study, the doublet of ixabepilone plus capecitabine was more effective than capecitabine alone in terms of progression-free survival and response rate, but this did not translate into an overall survival benefit.4

When triple-negative breast cancer patients respond to conventional chemotherapy with a pathologic complete response, good outcomes, including long-term survival, can be achieved. Nonresponse, on the other hand, is associated with poor outcomes.

Platinums are “natural candidates” for triple-negative breast cancer treatment, since they are DNA-damaging agents. Triple-negative breast cancer patients already have diminished capacity to repair DNA, especially those with basal-like tumors. Response rates of around 30% can be expected as first-line therapy with a platinum agent, with patients who have BRCA-mutated disease responding better (55%) than those with wild-type disease (26%).5,6

The tnAcity study is comparing nab-paclitaxel/gemcitabine, nab-paclitaxel/carboplatin, and gemcitabine/carboplatin; the best of the two nab-paclitaxel regimens will be compared to gemcitabine/carboplatin. The TNT/BRCA trial is comparing first-line carboplatin plus second-line docetaxel, vs the opposite sequence, in 400 patients.

“These are not targeted therapy studies, but while we are trying to identify subsets for targeted treatments, we still have to keep treating our patients. We can generate hypotheses for future studies from these datasets,” he said.

There is also strong rationale for PARP inhibitors in triple-negative breast cancer, which can overcome the disabling of the homologous combination repair mechanism in patients with BRCA-mutated disease. BRCA-deficient cells should be particularly sensitive to PARP inhibitors, and these drugs may sensitize cancer cells to DNA-damaging agents.

While a phase II study in 130 triple-negative breast cancer patients demonstrated the robust effect of adding a PARP inhibitor to gemcitabine/carboplatin,7 a subsequent phase III trial was negative.5 Nevertheless, there are a number of PARP inhibitors in development.

There are numerous potential targets in triple-negative breast cancer, which are being addressed by inhibitors of receptor tyrosine kinases, PI3K, AKT, mTOR, MEK, and other compounds, but no “home runs” yet. Immunotherapy may also be active in this tumor type. Multiple redundancies and pathway crosstalk may necessitate combination targeted therapy.

Good Research Platform

Since patients who achieve a pathologic complete response have better outcomes, neoadjuvant therapy may be a good research platform in triple-negative breast cancer. “As it stands now, patients who have less than a pathologic complete response should be enrolled on clinical trials,” he said.

In early-stage triple-negative breast cancer, the addition of carboplatin to neoadjuvant chemotherapy produced a pathologic complete response rate of 60% in the phase II CALGB/Alliance 40603 study.8 The rate was 46% for the control arm.

In the I-SPY 2 trial, veliparib plus carboplatin added to standard neoadjuvant chemotherapy improved pathologic complete response rates (52%) over chemotherapy alone (26%).9 The adaptive design of I-SPY 2 offers the chance to eliminate ineffective agents, “graduate” effective ones to phase III testing, and replace agents over time, he added.

In the phase II PrECOG 0105 trial, 36% of patients achieved a pathologic complete response to a combination regimen of carboplatin, gemcitabine, and iniparib, rising to 47% among ­BRCA-mutated patients and to 56% among triple-negative patients with BRCA mutations.10 Scores from the homologous recombination deficiency assay were significantly higher for responders than nonresponders (whether BRCA-mutated or wild-type), suggesting a potential means of identifying patients for platinum therapy.

A number of studies are underway evaluating treatments (cisplatin and the JAK2 inhibitor ruxolitinib [Jakafi] are two) in patients with residual disease following neoadjuvant chemotherapy, he added. ■

Disclosure: Dr. Jahanzeb reported no potential conflicts of interest.


1. Mayer IA, Abramson VG, Lehmann BD, et al: New strategies for triple-negative breast cancer—deciphering the heterogeneity. Clin Cancer Res 20:782-790, 2014.

2. Masuda H, Baggerly KA, Wang Y: Differential pathologic complete response rates after neoadjuvant chemotherapy among molecular subtypes of triple-negative breast cancer. 2013 ASCO Annual Meeting. Abstract 1005. Presented June 3, 2013.

3. Rugo HS, Barry WT, Moreno-Aspitia A, et al: CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). 2012 ASCO Annual Meeting. Abstract CRA1002. Presented June 4, 2012.

4. Rugo HS, Roche H, Thomas E, et al: Ixabepilone plus capecitabine vs capecitabine in patients with triple negative tumors: A pooled analysis of patients from two large phase III clinical studies. Cancer Res 69 (2 suppl 1): Abstract 3057, 2009.

5. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al: A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer. 2011 ASCO Annual Meeting. Abstract 1007. Presented June 6, 2011.

6. Isakoff SJ, Goss PE, Mayer EL, et al: TBCRC009: A multicenter phase II study of cisplatin or carboplatin for metastatic triple-negative breast cancer and evaluation of p63/p73 as a biomarker of response. Abstract 1025. 2011 ASCO Annual Meeting. Abstract 1025. Presented June 4, 2011.

7. 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.

8. 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: CALGB 40603 (Alliance). 2013 San Antonio Breast Cancer Symposium. Abstract S5-01. Presented December 13, 2013.

9. Rugo HS, Olopade O, DeMichele A, et al: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY2 trial. 2013 San Antonio Breast Cancer Symposium. Abstract S5-02. Presented December 13, 2013.

10. Telli ML, Jensen KC, Abkevich V, et al: Homologous recombination deficiency score predicts pathologic response following neoadjuvant platinum-based therapy in triple-negative and BRCA 1/2 mutation-associated breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract PD09-04. Presented December 13, 2012.