TNBC, which accounts for 10% to 20% of BC, is an aggressive form of BC that is estrogen and progesterone receptor-negative and human epidermal growth factor receptor 2-negative. It is difficult to treat, more often found in younger patients, has a higher rate of histological stage III and lymph node involvement, and is associated with rapid recurrence, short disease-free survival, and distant metastases. About 15% to 20% of patients with TNBC have a BRCA1/2 mutation, a susceptibility gene for BC, that occurs more often in TNBC than in other BC subtypes.
The mainstay of therapy for TNBC is neoadjuvant chemotherapy typically with anthracycline or taxane monotherapy or combination therapy as well as methotrexate, fluorouracil, and capecitabine.
Two recent papers—a systematic review and meta-analysis of randomized, controlled trials (RCTs) and a systematic review and meta-analysis of TNBC patients with BRCA1/2 mutations—examined the use of platinum-based adjuvant therapy in this BC subtype. Platinum-based drugs (i.e., cisplatin and carboplatin) inhibit the replication of DNA double-strands by inducing DNA strand breaks. Patients with BRCA1/2 mutations are susceptible to DNA damaging agents because they have DNA repair deficiencies.
The systematic review and meta-analysis of RCTs identified 19 studies that evaluated the efficacy of platinum-based regimens for treating patients with TNBC. Literature searches were conducted of Ovid, Medline, Embase, PubMed, Cochrane Database through July 24, 2022; Google Scholar and oncological-related websites were also analyzed.
To be included in the systematic review and meta-analysis, studies had to have a platinum and nonplatinum neoadjuvant therapy arm; be RCTs; the diagnosis of TNBC had to be confirmed by pathological examination and immunohistochemistry; and pathological complete remission (pCR) had to be a treatment outcome. Case report, retrospective cohort, or case-control studies were excluded as were any studies in which data from the original article was unavailable, the cancer type was not TNBC, there was no comparison between platinum and nonplatinum neoadjuvant regimens, and the articles were not in English.
Investigators found that platinum-based regimens were associated with a significantly higher pCR compared with all nonplatinum-based regimens (49.8% vs. 36.4% respectively; odds ratio [OR] 1.27; 95% CI, 1.14-1.43, P <.001). When anthracycline and taxane nonplatinum-based regimens were compared with platinum-based regimens, the OR was significant at 1.30 (95% CI, 1.12-1.51, P <.001).
Adverse events differed between platinum and nonplatinum-based regimens with the former group experiencing a higher percentage of neutropenia (51.5% vs. 47.0%, respectively; OR 1.27; 95% CI, 1.01-1.58, P = .037) and the latter group having more nausea and vomiting (29.4% vs. 24.4%, respectively; OR 0.88; 95% CI, 0.78-0.99). There was no difference in thrombocytopenia or diarrhea between the two treatment groups. Relapse-free survival was better in the platinum-treated group than in the nonplatinum-treated group (hazard ratio [HR] 0.78; 95% CI, 0.63-0.95, P = .016), but there was no difference in overall survival. This study also looked at BRCA mutations and found that TNBC patients with a BRCA mutation treated with a platinum-based regimen had a significantly higher pCR compared with those receiving nonplatinum-based regimens (OR 1.20; 95% CI, 1.02-1.41, P = .030)
The systematic review and meta-analysis that focused on whether BRCA1/2 mutations predicted response to platinum-based therapy in patients with TNBC included 22 studies and 2,158 patients with TNBC, of which 18% (or 392) had the BRCA1/2 mutation gene. These authors searched PubMed, Medline, and Cochrane Database up until March 2022. They found that platinum-containing neoadjuvant regimens were associated with a higher pCR and residual cancer burden (RCB) in patients with BRCA1/2 mutation TNBC. While pCR was 50.6% for the total group, it was 64.7% in BRCA1/2 mutation and 47.1% in wild-type groups.
RCB is a prognostic factor for distant recurrence-free survival in early BC, with RCB0/1 representing a favorable pathological response. While RCB0/1 reached 52.5% for the full group, it was 76.7% in the BRCA1/2 mutation and 47.0% in the wild-type groups, respectively. However, a platinum-based regimen was not associated with a prolonged disease-free survival benefit in TNBC patients with the BRCA1/2 mutation. Objective remission rates (ORR) and overall survival were improved in patients with BRCA1/2 mutation advanced TNBC who received platinum therapy. In the overall group, the ORR was 41.8% and was 67.1% in the BRCA1/2 mutation group but only 37.3% in the wild-type group (HR 1.91; 95% CI, 1.48-2.47; P <.00001). Progression-free survival and overall survival were significantly higher in the BRCA1/2 mutation group.
This article provides pharmacists caring for patients with TNBC evidence of an additional treatment modality in the management of a very difficult to treat condition, especially among those with the BRCA1/2 mutation.
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