Neoadjuvant Cisplatin Not Superior to Standard Chemo in BRCA+ HER2-Negative Breast Cancer

Nadine M. Tung, MD

Single-agent cisplatin did not lead to significantly higher pathologic complete response (pCR) rates or improved residual cancer burden (RCB) scores compared with doxorubicin plus cyclophosphamide in the neoadjuvant setting for patients with stage I to III HER2-negative breast cancer who harbor BRCA mutations.¹

Results showed that the pCR rate was 18% in the cisplatin arm and 26% in the doxorubicin/cyclophosphamide arm, leading to a risk ratio (RR) of 70% (90% CI, 0.39-1.2) The risk of RCB 0/1 in the cisplatin arm and doxorubicin/cyclophosphamide arm was 33% and 46%, respectively (RR, 0.73; 90% CI, 0.50-1.1).

These findings were similar in patients specifically with triple-negative breast cancer (TNBC), as well.

“Previous studies reported that the platinum-based therapy cisplatin was effective in BRCA carriers with breast cancer,” lead investigator Nadine Tung, MD, director of the Cancer Risk and Prevention Program, head of Breast Medical Oncology, Beth Israel Deaconess Medical Center, stated in a press release. “Those findings left clinicians uncertain whether to use cisplatin—an unconventional drug for treating early-stage breast cancer—or whether to use the same chemotherapy regimen used for other women with breast cancer. Prior to INFORM, no randomized prospective data existed comparing platinum to standard chemotherapy in this population of patients. Our study found that platinum-based therapy was actually no more effective than the standard first-line treatment.”

BRCA mutations are identified in up to 5% of all breast cancer cases, and make up a larger proportion of breast cancer in younger women, Jewish women, and those with a family history of breast cancer. Moreover, BRCA mutations are identified in 10% to 20% of patients with TNBC.

In the multicenter, phase II, INFORM trial, investigators randomized 117 newly diagnosed patients 1:1 to receive either neoadjuvant cisplatin at 75 mg/m² every 3 weeks for 4 doses (n = 60), or doxorubicin at 60 mg/m² plus cyclophosphamide at 600 mg/m² every 2 to 3 weeks for 4 doses (n = 57). All patients then underwent mastectomy or lumpectomy, followed by lymph node biopsy or dissection after completing their respective treatments. A tumor size of ≥1.5 cm was required.

Patients must have also had an ECOG performance status of 0 or 1, as well as adequate hematologic, renal, hepatic, and cardiac function. Patients with grade ≥2 baseline neuropathy were excluded from enrollment.

The mean age of patients was 42 years (range, 24-73 years). Sixty-nine percent of patients had BRCA1 mutations, 30% had BRCA2 mutations, and 2% of patients had both mutations. Patients were categorized as either having stage I (19%), II (63%), or III disease (18%), and 45% of patients had nodal involvement at baseline. Using a 10% cutoff to define TNBC, 70% of the overall population had TNBC; 30% of patients had hormone receptor—positive, HER2-negative breast cancer.

After enrolling 97 patients, there was an amendment to the study in December 2017 to allow patients with T size ≥1.0 cm and prior chemotherapy, excluding anthracycline or platinum-based chemotherapy, in an effort to increase accrual.

The primary endpoint was pCR; superiority was determined if the pCR rates were ≥20% higher with cisplatin versus doxorubicin/cyclophosphamide. Secondary endpoints included RCB of 0 or 1 and safety. In The University of Texas MD Anderson Cancer Center RCB index, a score of 0 equates to a pCR and RCB-I equates to minimal burden.

Additional results showed that for patients with TNBC, the RR was 0.79 (90% CI, 0.42-1.5) for attaining pCR with cisplatin compared with doxorubicin/cyclophosphamide. The RR was 0.30 (90% CI, 0.05-1.7) for those with estrogen receptor (ER)—positive/HER2-negative disease.

For patients with TNBC, the rate of RCB 0/1 was 36% with cisplatin and 47% with doxorubicin/cyclophosphamide. For patients with ER-positive/HER2-negative disease, the rate of RCB 0/1 was 25% with cisplatin and 42% with doxorubicin/cyclophosphamide. Eleven patients could not have an RCB score assigned because they received either more or less than the 4 protocol-assigned chemotherapy cycles.

Regarding safety, there were 11 nonhematologic grade ≥3 toxicities in 60 patients receiving cisplatin: nausea/vomiting (n = 3), increased creatinine (n = 2), thromboembolic event (n = 2), fatigue (n = 1), tinnitus (n = 1), pulmonary hypertension (n = 1), and hyperglycemia (n = 1).

Four patients experienced nonhematologic toxicities of grade ≥3 while being treated with doxorubicin/cyclophosphamide: fatigue (n = 1), nausea (n = 1), diarrhea (n = 1), and headache (n = 1). Grade 3/4 neutropenia was experienced by 7% of patients receiving cisplatin and 5% receiving doxorubicin/cyclophosphamide; 3% of patients in the cisplatin arm and 10% in the doxorubicin/cyclophosphamide arm experienced ≥1 episode of febrile neutropenia.

“The INFORM trial demonstrates that the pathologic response with [doxorubicin/cyclophosphamide] is at least as good as that achieved with cisplatin in this population. Both regimens demonstrate activity, and chemotherapy choice may need to incorporate individual comorbidities as well as anticipated toxicities with each regimen,” Tung and coinvestigators concluded.

References

1. Tung N, Arun B, Hacker MR, et al. TBCRC 031: Randomized phase II study of neoadjuvant cisplatin versus doxorubicin-cyclophosphamide in germline BRCA carriers with HER2-negative breast cancer (the INFORM trial) [published online ahead of print February 25, 2020]. J Clin Oncol. doi: 10.1200/JCO.19.03292
2. Platinum-based agents are not superior to standard chemotherapy for patients with breast cancer who carry BRCA mutations [news release]. Beth Israel Deaconess Medical Center. Published March 4, 2020. https://bit.ly/38A8iWR. Accessed March 6, 2020.