The treatment of triple-negative breast cancer is rapidly evolving, as clinical trials continue to test chemotherapy agents and combinations and immunotherapy studies promise potentially “game-changing” interventions early in the course of disease, Joyce O’Shaughnessy, MD, reported at the 19th Annual Lynn Sage Breast Cancer Symposium in Chicago.¹ “To date, there are no targeted therapies that we have specifically for triple-negative breast cancer, although hopefully, we will see that change in the very near future,” she added. Dr. O’Shaughnessy holds the Celebrating Women Chair in Breast Cancer Research, Texas Oncology–Baylor Charles A. Sammons Cancer Center, Dallas, and The US Oncology Network. 

Optimal Chemotherapy Uncertain

“Optimal curative chemotherapy for triple-negative breast cancer is still uncertain,” Dr. O’Shaughnessy said. A joint efficacy analysis of the ABC Trials comparing a nonanthracycline regimen of the taxane docetaxel and cyclophosphamide (TC) vs standard chemotherapy with doxorubicin and cyclophosphamide (AC) plus a taxane (TaxAC or TAC) showed that invasive disease–free survival favored the anthracycline-containing regimens. The 4-year invasive disease–free survival rate was 90.7% for the anthracycline regimens vs 88.2% vs standard chemotherapy.² 

To date, there are no targeted therapies that we have specifically for triple-negative breast cancer, although hopefully, we will see that change in the very near future.

— Joyce O’Shaughnessy, MD

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“Particularly in the triple-negative population [31% of total patients], the hazard ratio was definitively in favor of the anthracycline-based regimen,” Dr. O’Shaughnessy commented. “The conclusion from this trial was that the TaxAC regimen remains the standard of care for high-risk early breast cancer, particularly for triple-negative cases and patients with very high-risk hormone receptor–positive disease.”

Contradictory data come from the West German Study Group phase III PlanB trial,³ which compared TC vs the anthracycline epirubicin and cyclophosphamide followed by docetaxel in patients with early-stage triple-negative breast cancer. “For disease-free survival, there was absolutely no difference between the anthracycline arm and the docetaxel/cyclophosphamide arm [89.9 % vs 90.2%],” Dr. O’Shaughnessy noted. Overall survival neared 95% for both groups. 

“So why the different results between the ABC and PlanB trials? The PlanB trial had a lower-risk population. A greater percentage of patients had node-negative disease, and a smaller percentage of patients had triple-negative disease,” Dr. O’Shaughnessy said. “The bottom line for the clinic is that for lower-risk hormone receptor–positive disease where chemotherapy is indicated at all, TC seems reasonable; however, for all but the lowest-risk triple-negative breast cancer patients, chemotherapy should include an anthracycline and a taxane.” 

Residual Cancer Burden

“Patients with minimal disease remaining after surgery (residual cancer burden [RCB]-I) do as well as patients with RCB-0—ie, those who are completely negative for disease in their breast and axilla,” Dr. O’Shaughnessy explained. “Those with RCB-II or RCB-III do very poorly, and that is where our efforts need to be—to understand the biology of those patients and to get more patients into the RCB-0 or RCB-I categories. 

For patients with germline BRCA-mutated disease, “it is reasonable to consider a platinum-based regimen in the first-line setting, but for patients with wild-type disease, one could go either way, and a taxane would certainly be reasonable,” she said. “Some patients with metastatic triple-negative breast cancer are exceptional responders to first-line platinum therapy. These patients have a specific clinical phenotype,” she noted. “The site of disease is not bone or liver, but lung, lymph node, breast, or chest wall…. So, if you see these patients in your clinic, it is not unreasonable to consider a platinum-based regimen.”

If Doublets Are Needed

Patients with first-line metastatic triple-negative breast cancer or heavy tumor burdens may require doublet chemotherapy, and several different doublets have been studied.

A study of patients with metastatic triple-negative breast cancer found that those randomized to nanoparticle albumin-bound (nab)-paclitaxel (Abraxane)/carboplatin had a median progression-free survival of 7.4 months vs 5.4 months for those receiving nab-paclitaxel with gemcitabine and 6.0 months for those receiving gemcitabine/carboplatin—statistically significant differences.⁴ “Certainly nab-paclitaxel/carboplatin would be a reasonable choice for patients who require a doublet in the first-line setting because of very significant tumor burden or severe end-organ function,” Dr. O’Shaughnessy stated. 

In the GeparSixto trial, patients received bevacizumab -(Avastin), paclitaxel, and nonpegylated liposomal doxorubicin, with or without carboplatin. The addition of carboplatin improved the pathologic complete response rate in the breast and lymph nodes by 16%, which was “highly significant,”⁵ she said.

In the Cancer and Leukemia Group B (CALGB) 40603 trial, patients who received carboplatin in addition to paclitaxel with or without bevacizumab had a 13% improvement in pathologic complete response rate (54% with carboplatin vs 41% without) in the breast and axilla, and that was statistically significant,” Dr. O’Shaughnessy noted. The 3-year disease-free survival rates were significantly superior with the addition of carboplatin. “Updated data show that for distant disease–free survival at the 4-year mark, the hazard ratio is 0.5 in favor of carboplatin, and that is statistically significant,” she added. 

The phase III Brightness trial comparing neoadjuvant therapy with the investigational poly(ADP-ribose) polymerase (PARP) inhibitor veliparib and carboplatin/paclitaxel vs placebo and carboplatin/paclitaxel vs placebo and placebo/paclitaxel found the pathologic response rate was 26% higher with the addition of carboplatin to paclitaxel, and the addition of veliparib did not make any difference,⁶ Dr. O’Shaughnessy said. “We need more follow-up on this, but these data add some additional credence to the idea of considering the use of a preoperative carboplatin if one is going to start with weekly paclitaxel, as many of the clinical trials have been doing.” 

Preoperative Nonanthracycline Chemotherapy

Dr. O’Shaughnessy highlighted other data sets clinicians should be aware of because they have “some potential clinical utility” for the preoperative use of nonanthracycline chemotherapy.

In the WSG-ADAPT TN trial, patients randomized to neoadjuvant therapy with nab-paclitaxel and -carboplatin had a 46% pathologic complete response rate—“lower than we’ve been seeing, around 55%, probably because it was just four cycles of therapy,” Dr. O’Shaughnessy noted. Patients randomized to nab-paclitaxel and gemcitabine had a 29% pathologic complete response rate and greater toxicity.⁷

In the ongoing NRG-BR003 trial, patients with node-positive or high-risk node-negative triple-negative breast cancer are being randomized to AC and paclitaxel with or without carboplatin. While this study is looking for “the definitive answer” about whether carboplatin will improve patient outcome, “in the meantime, it is reasonable to recommend the addition of preoperative carboplatin to patients with high-risk triple-negative breast cancer,” Dr. O’Shaughnessy said. 

The CREATE-X study looked at whether preoperative therapy can decrease the risk of recurrence in patients without a pathologic complete response.⁸ Patients were randomized to standard therapy with or without 6 months of full-dose capecitabine. In the overall treated population, both disease-free and overall survival “were statistically significantly in favor of the addition of capecitabine for six cycles in this very high-risk group of patients, particularly in those with triple-negative breast cancers,” Dr. O’Shaughnessy reported. “It is reasonable to utilize capecitabine for triple-negative breast cancer patients and others without a pathologic complete response,” she said. 

Looking Ahead

“Transitioning to what’s next, I really hope within a year from now, we will have the data and perhaps even the U.S. Food and Drug Administration approval for an inhibitor of programmed cell death protein 1 (PD-1) or its ligand 1 (PD-L1) in the treatment of metastatic triple-negative breast cancer, because these antibodies against PD-L1 and PD-1 can stop the negative regulation that prevents T cells from recognizing and killing triple-negative breast cancers,” Dr. O’Shaughnessy said. 

For germline BRCA metastatic disease, PARP inhibitors in the first-line setting “may be platinum-sparing,” Dr. O’Shaughnessy said. “Ongoing studies combining PARP inhibitors with checkpoint inhibitors are very interesting. AKT and androgen receptors are also very important targets in triple-negative breast cancer,” she said.

“Triple-negative breast cancer is a very good target for immunotherapy, probably particularly early in the course of the disease. Phase III trials, some nearing completion, could result in the first approvals of immunotherapy for metastatic triple-negative breast cancer, which would be a game-changing step forward,” Dr. O’Shaughnessy stated. ■

DISCLOSURE: Dr. O’Shaughnessy has consulted for Arno Therapeutics, AstraZeneca, Celgene, Corcept Therapeutics, Eisai, Genentech, GSK, Lilly, J&J, Merrimack, Novartis, Pfizer, Roche, Sanofi, Takeda, and Medfusion.

REFERENCES

1. O’Shaughnessy J: Triple-negative breast cancer: Where are we now? 2017 Lynn Sage Breast Cancer Symposium. Presented September 15, 2017.

2. Blum JL, et al. J Clin Oncol 35:2647-2655, 2017.

3. Harbeck N, et al: Prospective WSG phase III PlanB trial. 2017 ASCO Annual Meeting. Abstract 504. Presented June 5, 2017.

4. Yardley D, et al. 2016 San Antonio Breast Cancer Symposium. Abstract 874. Presented December 9, 2016.

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

6. Geyer CE, et al: Phase 3 study evaluating efficacy and safety of veliparib plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy in patients with early stage triple-negative breast cancer. 2017 ASCO Annual Meeting. Abstract 520. Presented June 4, 2017.

7. Gluz O, et al: Comparison of 12 weeks neoadjuvant nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple-negative breast cancer. 2015 San Antonio Breast Cancer Symposium. Abstract S6-07. Presented December 11, 2015.

8. Masuda N, et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376:2147-2159, 2017.