In a phase III randomized trial conducted in India, the addition of weekly carboplatin to standard taxane/anthracycline–based neoadjuvant chemotherapy improved pathologic complete response rates, event-free survival, and overall survival in patients with triple-negative breast cancer patients aged ≤ 50 years, investigators reported at the 2022 San Antonio Breast Cancer Symposium.1
As reported by researchers from Tata Memorial Centre, Mumbai, the addition of carboplatin to neoadjuvant chemotherapy in younger patients resulted in an 18.5% absolute increase in pathologic complete response rates (P < .001), a 12.5% absolute increase in event-free survival (P = .004), and an 11.2% absolute increase in overall survival (P = .003).
“The addition of carboplatin to taxane/anthracycline neoadjuvant chemotherapy should be the standard treatment in patients with triple-negative breast cancer who are 50 years old or younger or who are premenopausal,” said Sudeep Gupta, MD, Director and Professor of Oncology at Tata Memorial Centre, who presented the findings.
Sudeep Gupta, MD
“There was a statistically significant interaction between age/menopausal status and the effect of carboplatin and no interaction with family history, stage, tumor size, or clinical nodal status in the modified intention-to-treat population. The precise reasons for the interaction between age/menopausal status and carboplatin are unclear,” he said.
“A long-standing question has been about the benefit of adding platinum in the adjuvant or neoadjuvant setting in triple-negative breast cancer. Some recent immune checkpoint inhibitor–based studies have already incorporated these agents as part of the chemotherapy backbone. Previous phase II studies have suggested an increase in pathologic response with the addition of neoadjuvant platinum, but they were underpowered for survival. In particular, the GeparSixto2 and BrighTNess3 trials showed an increase in event-free survival with the addition of carboplatin, but the CALGB 40603 study4 did not,” Dr. Gupta said.
About the Study
The study of 720 patients, which was powered for event-free survival, was conducted to provide a definitive answer to the important clinical question as to the value of neoadjuvant platinum in this breast cancer subtype. Participants had triple-negative breast cancer, clinical T stage 1 to 4, clinical nodal status 0 to 3, and no evidence of metastatic disease. About 70% of patients were ≤ 50 years old, and 60% were premenopausal. Approximately 60% had locally advanced disease, 88% had node-positive disease, and 77% had tumors larger than 5 cm, reflecting a “higher-risk population of triple-negative breast cancer,” Dr. Gupta noted.
Patients were randomly assigned to receive paclitaxel at 100 mg/m2 with or without carboplatin at AUC2 given once per week for 8 weeks, followed by four cycles of standard anthracycline/cyclophosphamide, then surgery and radiotherapy. The primary endpoint of the study was event-free survival, and key secondary endpoints were overall survival and pathologic complete response.
Carboplatin Improved Outcomes in Younger Patients
In the modified intention-to-treat population of 717 patients, the addition of weekly carboplatin resulted in an absolute increase of 6.6% in 5-year event-free survival based on rates of 64.1% in the control arm and 70.7% in the platinum arm (hazard ratio [HR] = 0.798; P = .081). Analysis by age showed a 12.5% absolute increase in patients aged ≤ 50 years (HR = 0.642; P = .004), with no benefit observed in patients older than age 50.
Carboplatin also produced a statistically significant 14.2% increase in pathologic complete response in the breast and lymph nodes. This outcome was achieved by 40.3% of the control arm and 54.5% of the platinum arm (P < .001), with the benefit again driven by younger patients, whose rate was 41.5% vs 61.0%, respectively (P < .001) compared with 37.5% vs 38.1%, respectively, in the older cohort (P = 1.0).
Improvement in Overall Survival
Patients in the platinum arm experienced an absolute 7.6% increase in overall survival at 5 years, based on rates of 66.8% in the control arm and 74.4% in the platinum arm (HR = 0.74; P = .029). Again, benefit was limited to the patients aged ≤ 50 years, who demonstrated an 11.2% increase in overall survival, with a rate of 65.9% vs 77.1%, respectively (HR = 0.611; P = .003). Carboplatin did not improve overall survival in the older cohort.
The achievement of pathologic complete response was “powerfully prognostic” for both event-free and overall survival in both the younger and older cohorts, with absolute increases exceeding 30% in both age groups among subsets achieving pathologic complete responses.
“Our survival results are concordant with GeparSixto2 and BrighTNess3 but discordant with CALGB 40603,”4 Dr. Gupta noted. One reason for the discrepancy could pertain to the use of weekly carboplatin (as in GeparSixto), “which likely increased compliance and reduced toxicity,” he suggested. The investigators also used the standard chemotherapy backbone of taxane, anthracycline, and cyclophosphamide but did not use bevacizumab or PARP inhibitors.
There was no difference in toxicity and treatment compliance between younger and older patients. The platinum arm did have more patients with grade ≥ 3 neutropenia, anemia, thrombocytopenia, and febrile neutropenia, but nonhematologic toxicity rates were similar.
DISCLOSURE: Dr. Gupta reported no conflicts of interest.
REFERENCES
1. Gupta S, Nair NS, Hawaldar RW, et al: Addition of platinum to sequential taxane-anthracycline neoadjuvant chemotherapy in patients with triple-negative breast cancer: A phase III randomized controlled trial. 2022 San Antonio Breast Cancer Symposium. Abstract GS5-01. Presented December 9, 2022.
2. Loibl S, Weber KE, Timms KM, et al: Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response: Final results from GeparSixto. Ann Oncol 29:2341-2347, 2018.
3. Geyer CE, Sikov WM, Huober J, et al: Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial. Ann Oncol 33:384-394, 2022.
4. Shepherd JH, Ballman K, Polley MYC, et al: CALGB 40603 (Alliance): Long-term outcomes and genomic correlates of response and survival after neoadjuvant chemotherapy with or without carboplatin and bevacizumab in triple-negative breast cancer. J Clin Oncol 40:1323-1334, 2022.
