Treatment for Triple-Negative Breast Cancer Slowly Moving Forward

March 26, 2018

Triple-negative breast cancer treatments being investigated include checkpoint inhibitors, agents that target the androgen receptor pathways, and antibody-drug conjugates.

Triple-negative breast cancer (TNBC) is an aggressive subtype, and metastatic disease is difficult to treat. It tends to have the worst prognosis among the major subtypes of breast cancer, due to both limitations in understanding of the underlying biology and the lack of targeted therapeutic agents. Currently, cytotoxic chemotherapy remains the mainstay of systemic treatment, although studies are investigating the use of other drug classes, including checkpoint inhibitors, agents that target the androgen receptor pathways, and antibody-drug conjugates.

During a presentation at the National Comprehensive Cancer Network (NCCN) Annual Conference, held March 22–24 in Orlando, Florida, Anthony D. Elias, MD, of the University of Colorado Cancer Center, explained that there “aren’t any substantive additions to the NCCN guidelines for TNBC.” He noted that with the exception of olaparib for the treatment of tumors with the germline BRCA mutations, there are no approved targeted therapies in this setting, leaving chemotherapy as the only option.

“It is important to remember that TNBC is very heterogeneous, and it is an area that we are still trying to discover,” Elias explained. “We do know that BRCA status is a validated subset.”

Other subtypes include basal-like, immunomodulatory, mesenchymal, mesenchymal stem-like, and luminal androgen receptor, and subtype may affect response to neoadjuvant chemotherapy.

Current NCCN guidelines suggest that the use of adjuvant therapy for the T1a/bN0 TNBC, although other factors such as age (< 35, age > 70), multifocality, lymphovascular invasion, and comorbidities also need to be considered.

As far as the optimal regimen, Elias explained that the ABC trial, which compared a nonanthracycline regimen consisting of docetaxel and cyclophosphamide vs standard chemotherapy with doxorubicin and cyclophosphamide plus a taxane showed that invasive disease-free survival (DFS) favored the anthracycline-containing regimens. The 4-year DFS rate was 90.7% for the anthracycline regimens compared with 88.2% with standard chemotherapy.

“However, I would argue that the anthracycline does contain irreversible toxicities,” said Elias. These include cardiomyopathy (0.5% to 1% risk) and leukemia (0.5% to 1% risk), and anthracyclines should be used only if the estimated added benefit outweighs the absolute increased risk of these toxicities.

When looking at neoadjuvant therapy, studies have shown improved DFS and overall survival for locally advanced/invasive breast cancer, and breast-conserving surgery and/or axillary surgery may be facilitated. The extent of residual disease at surgery may guide future therapy, Elias explained, but also cautioned against the risk of possible overtreatment if the clinical stage is overestimated.

He also noted that the use of platinum drugs in this setting is controversial, but that there have been three trials looking at the addition of carboplatin to paclitaxel. Only one showed improved DFS, there was substantial toxicity, and none have shown a survival benefit. However, Elias pointed out that “in all fairness, they weren’t powered to do so.”

Guidelines now suggest that for metastatic TNBC, first‐line chemotherapy should be with a taxane or anthracycline if the agents were not previously used in the adjuvant or neoadjuvant setting. The preferred taxane is weekly paclitaxel and sequential single agents are preferred unless there is a visceral crisis. While combination regimens have demonstrated higher response rates, they did not lead to significant improvements in survival.

Elias also noted that in this population, eribulin, capecitabine, and platins were likely to be more effective than gemcitabine and vinorelbine, but the line of therapy may actually be more predictive of a response. “Chemotherapy resistance develops quickly and third and fourth lines of therapy have very short median progression-free survivals and response rates,” he said.

Studies have shown that platinum drugs are effective in BRCA‐mutated TNBC in the neoadjuvant setting. One trial demonstrated that single-agent cisplatin (75 mg/m2) given every 3 weeks resulted in a partial response in 61% of patients and 56% of estrogen receptor–positive patients. “The presence of germline mutations are the dominating factor in terms of the utility for platinum drugs,” he said. “But some questions remain, such as the benefit of cisplatin vs carboplatin.”

PARP inhibitors have demonstrated efficacy in patients with BRCA1 and BRCA2 mutations, and they are the only targeted agent thus far for TNBC. Olaparib is approved for the treatment of previously treated metastatic disease with a germline mutation, but not with a somatic mutation or low expression of BRCA. In a recent trial, olaparib (300 mg bid) compared with physician’s choice of single-agent chemotherapy in TNBC patients (~50% had a confirmed BRCA mutation) showed a more favorable median progression-free survival: 7.0 months vs 4.2 months (hazard ratio, 0.58; 95% CI, 0.43–0.80).

Similar data were seen for another agent, talazoparib, explained Elias. But this also brings up other questions. The PARP inhibitors are active therapeutic agents, so should all patients with metastatic breast cancer be tested for BRCA mutations? He also cautioned that a survival advantage has not yet been documented.

Future directions in TNBC include combination therapies using multiple agents and moving to earlier-stage disease. A variety of different agents are also being investigated. Immune checkpoint inhibitors are of interest, and several ongoing studies are investigating the use of pembrolizumab, atezolizumab, and avelumab for this population. Other drugs that may be effective in this population that are currently being studied include SGN-LIV1A, a humanized IgG1 anti‐LIV1 monoclonal antibody linked to monomethyl auristatin E, glembatumumab vedotin, and sacituzumab govitecan.

About 12% to 55% of TNBCs express androgen receptors, Elias noted, and this is another area of active investigation. Currently, several drugs that are used in prostate cancer are being studied in this population, including bicalutamide and enzalutamide.

Finally, Elias said that he had to “put in a plug for exercise,” since regular exercise can reduce all‐cause mortality and disease‐specific mortality.