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Neoadjuvant cisplatin fails to beat standard AC in HER2-negative breast cancer



– For patients with newly diagnosed HER2-negative breast cancer who are BRCA carriers, neoadjuvant cisplatin does not offer a higher pathologic complete response (pCR) rate than standard doxorubicin/cyclophosphamide (AC), based on results from the phase 2 INFORM trial.

Will Pass/MDedge News

Dr. Nadine Tung

Findings from this trial and others suggest that BRCA deficiency may be a marker of sensitivity to DNA-damaging chemotherapy generally, instead of platinum agents specifically, reported lead author Nadine Tung, MD, of Beth Israel Deaconess Medical Center in Boston.

While single-agent platinum chemotherapy has shown significant clinical activity in the neoadjuvant and metastatic settings for BRCA-mutated triple-negative breast cancer (TNBC), prospective trials comparing platinum-based therapy with non–platinum-based therapy have been lacking, Dr. Tung said during a presentation at the San Antonio Breast Cancer Symposium.

“Almost no data exist for the response to platinum agents among BRCA carriers with hormone receptor–positive breast cancer,” Dr. Tung said.

The investigators aimed to address both of these knowledge gaps with a head-to-head trial. Although the investigators aimed for an accrual of 170 participants, all newly diagnosed patients, only 118 were enrolled, of whom 117 were included in the final analysis. All patients had HER2-negative breast cancer with at least one germline BRCA mutation. About two-thirds of patients (69%) were BRCA1 positive, about one-third (30%) were BRCA2 positive, and the small remainder (2%) had both mutations. Clinical stage proportions were as follows: I (19%), II (63%), and III (18%). Almost three-fourths of patients (70%) had TNBC, and 45% had nodal involvement upon enrollment.

Patients were randomized at a 1:1 ratio to receive either cisplatin (75 mg/m2 every 3 weeks for four cycles) or standard AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2-3 weeks for four cycles). These treatments were followed by surgery. The primary endpoint was pCR . Secondary endpoints included residual cancer burden of 0-1 (RCB 0/1), 3-year disease-free survival, and toxicities.

Most patients completed the regimens as planned; however, seven patients received more than four cycles of chemotherapy while four patients completed fewer than four cycles. These 11 patients were categorized as not having a pathologic complete response.

Among the remaining patients, platinum-based chemotherapy was associated with an 18% pCR rate, compared with 26% for standard AC, which translated to a risk ratio of 0.70 that was not significant. Among patients with TNBC (n = 82), pCR rates followed a similar trend (22% vs. 28%), again without statistical significance. For patients with estrogen receptor–positive disease, the numerical disparity in pCR rate was greater (cisplatin at 6% vs. AC at 21%); however, once more, this difference was not statistically significant. Because of the small number of patients in this subgroup (n = 35), Dr. Tung advised that results be interpreted with caution.

Results for RCB 0/1 were similar to pCR. AC was associated with a higher rate of RCB 0-1 for all patients (46% vs. 33%), patients with TNBC (47% vs. 36%), and patients with hormone receptor–positive disease (42% vs. 25%). Across all patients and subtypes, these differences were not statistically significant.

Safety profiles were similar to previously published data for both regimens.

“In conclusion, contrary to our initial expectations, the pCR rate and RCB 0/1 rate is not significantly higher after cisplatin than after AC in BRCA carriers with early-stage breast cancer, whether triple-negative or estrogen receptor–positive HER2-negative disease,” Dr. Tung said. “Our statistician has concluded that there is no realistic scenario by which the pCR with cisplatin would have been significantly higher than with AC had this study met its accrual.”

“We believe the results of the INFORM trial are consistent with those of the GeparSixto and BrightTNess neoadjuvant trials,” Dr. Tung said. “One interpretation of the INFORM trial results, as well as these two trials, is that breast cancer in BRCA carriers is more sensitive than in noncarriers to DNA-damaging agents. … BRCA deficiency or homologous combination deficiency may simply be a marker of sensitivity to DNA-damaging chemotherapy rather than platinum agents specifically.”

The investigators disclosed relationships with Merck, AstraZeneca, Genentech, and others.

SOURCE: Tung N et al. SABCS 2019, Abstract GS6-03.

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