Commentary: Genetic variants, ovarian suppression, and metabolic syndrome in BC, February 2023

Poly-(ADP-ribose) polymerase (PARP) inhibitors have emerged as essential therapeutic agents in patients with germline BRCA1/2-mutated BC. A BRCA-like phenotype is displayed by a large subset of patients with germline BRCA1/2-wildtype BC who present with homologous recombination deficiency (HRD). The randomized phase 2 S1416 trial (Rodler et al) evaluated the efficacy of cisplatin combined with the PARP inhibitor veliparib in three cohorts of metastatic BC: mutated germline BRCA1/2, BRCA-like, and non-BRCA–like. A total of 335 patients with metastatic or recurrent triple-negative BC (TNBC) or germline BRCA1/2-mutated metastatic BC were randomly assigned (1:1) to receive cisplatin plus either veliparib or a matching placebo. The findings showed that the addition of veliparib to cisplatin significantly improved progression-free survival (PFS) in patients with BRCA-like metastatic TNBC compared with placebo (5.9 vs 4.2 months; HR 0.57; log-rank P = .01), but not in mutated germline BRCA1/2 (6.2 vs 6.4 months; P = .54) and non-BRCA–like (4.0 vs 3.0 months; P = .57) groups. No new toxicity signals were observed. These findings suggest BRCA-like TNBC might show sensitivity to PARP inhibitors and therefore these agents should be explored further in this cohort.

A recent update from the combined analysis of the SOFT and TEXT studies comparing outcomes in 4690 premenopausal women with estrogen/progesterone receptor–positive early BC (Pagani et al) showed that exemestane plus ovarian function suppression (OFS) led to a greater reduction in recurrence risk compared with tamoxifen plus OFS in premenopausal women. After a median follow-up of 13 years, results showed a 4.6% absolute improvement in 12-year disease-free survival (HR 0.79; P < .001) and a 1.8% absolute improvement in disease recurrence-free interval (HR 0.83; P = .03) with exemestane plus OFS compared with tamoxifen plus OFS. These treatment effects on recurrence began to attenuate over time, being strongest in the first 5 years with no further improvement after 10 or more years. No improvement in overall survival (OS) was noted with exemestane vs tamoxifen, although both arms had excellent survival outcomes (90.1% vs 89.1%; HR 0.93; 95% CI 0.78-1.11). It is important to note that there was a 3.3% absolute improvement in 12-year OS with exemestane plus OFS among patients with HER2-negative tumors who received chemotherapy. This OS benefit was also noted amongst patients with high-risk clinicopathologic characteristics (<35 years and those with > 2 cm or grade 3 tumors), ranging from 4.0% to 5.5% absolute improvement. In conclusion, sustained recurrence risk reductions were noted with adjuvant exemestane plus OFS compared with tamoxifen plus OFS, with the most clinically meaningful survival benefit noted for patients with higher risk tumors. Proper selection of patients who are most likely to benefit from exemestane over tamoxifen is vital to maximize the survival benefit while minimizing the burden of treatment intensification.

Findings from a retrospective study including 221 women with BC who received preoperative neoadjuvant chemotherapy (NAC) showed that the presence of metabolic syndrome (MetS) worsened survival outcomes and increased disease recurrence risk (Zhou et al). Patients were divided into MetS and non-MetS groups according to National Cholesterol Education Program Adult Treatment Panel III criteria to investigate the association between MetS and clinicopathologic characteristics, pathologic complete response (pCR), and long-term survival. The MetS group had a significantly lower likelihood of achieving pCR after NAC compared with the non-MetS group (odds ratio [OR] 0.316; P = .028), with the risk for death (OR 2.587; P = .004) and disease recurrence (OR 2.228; P = .007) being significantly higher in patients with vs without MetS. In a multivariate analysis, MetS (P = 0.028) and hormone receptors status were independent predictors of pCR after NAC in BC. These findings emphasize the importance of timely intervention of metabolic syndrome to improve outcomes in patients with BC.

Poly-(ADP-ribose) polymerase (PARP) inhibitors have emerged as essential therapeutic agents in patients with germline BRCA1/2-mutated BC. A BRCA-like phenotype is displayed by a large subset of patients with germline BRCA1/2-wildtype BC who present with homologous recombination deficiency (HRD). The randomized phase 2 S1416 trial (Rodler et al) evaluated the efficacy of cisplatin combined with the PARP inhibitor veliparib in three cohorts of metastatic BC: mutated germline BRCA1/2, BRCA-like, and non-BRCA–like. A total of 335 patients with metastatic or recurrent triple-negative BC (TNBC) or germline BRCA1/2-mutated metastatic BC were randomly assigned (1:1) to receive cisplatin plus either veliparib or a matching placebo. The findings showed that the addition of veliparib to cisplatin significantly improved progression-free survival (PFS) in patients with BRCA-like metastatic TNBC compared with placebo (5.9 vs 4.2 months; HR 0.57; log-rank P = .01), but not in mutated germline BRCA1/2 (6.2 vs 6.4 months; P = .54) and non-BRCA–like (4.0 vs 3.0 months; P = .57) groups. No new toxicity signals were observed. These findings suggest BRCA-like TNBC might show sensitivity to PARP inhibitors and therefore these agents should be explored further in this cohort.

A recent update from the combined analysis of the SOFT and TEXT studies comparing outcomes in 4690 premenopausal women with estrogen/progesterone receptor–positive early BC (Pagani et al) showed that exemestane plus ovarian function suppression (OFS) led to a greater reduction in recurrence risk compared with tamoxifen plus OFS in premenopausal women. After a median follow-up of 13 years, results showed a 4.6% absolute improvement in 12-year disease-free survival (HR 0.79; P < .001) and a 1.8% absolute improvement in disease recurrence-free interval (HR 0.83; P = .03) with exemestane plus OFS compared with tamoxifen plus OFS. These treatment effects on recurrence began to attenuate over time, being strongest in the first 5 years with no further improvement after 10 or more years. No improvement in overall survival (OS) was noted with exemestane vs tamoxifen, although both arms had excellent survival outcomes (90.1% vs 89.1%; HR 0.93; 95% CI 0.78-1.11). It is important to note that there was a 3.3% absolute improvement in 12-year OS with exemestane plus OFS among patients with HER2-negative tumors who received chemotherapy. This OS benefit was also noted amongst patients with high-risk clinicopathologic characteristics (<35 years and those with > 2 cm or grade 3 tumors), ranging from 4.0% to 5.5% absolute improvement. In conclusion, sustained recurrence risk reductions were noted with adjuvant exemestane plus OFS compared with tamoxifen plus OFS, with the most clinically meaningful survival benefit noted for patients with higher risk tumors. Proper selection of patients who are most likely to benefit from exemestane over tamoxifen is vital to maximize the survival benefit while minimizing the burden of treatment intensification.

Findings from a retrospective study including 221 women with BC who received preoperative neoadjuvant chemotherapy (NAC) showed that the presence of metabolic syndrome (MetS) worsened survival outcomes and increased disease recurrence risk (Zhou et al). Patients were divided into MetS and non-MetS groups according to National Cholesterol Education Program Adult Treatment Panel III criteria to investigate the association between MetS and clinicopathologic characteristics, pathologic complete response (pCR), and long-term survival. The MetS group had a significantly lower likelihood of achieving pCR after NAC compared with the non-MetS group (odds ratio [OR] 0.316; P = .028), with the risk for death (OR 2.587; P = .004) and disease recurrence (OR 2.228; P = .007) being significantly higher in patients with vs without MetS. In a multivariate analysis, MetS (P = 0.028) and hormone receptors status were independent predictors of pCR after NAC in BC. These findings emphasize the importance of timely intervention of metabolic syndrome to improve outcomes in patients with BC.

Poly-(ADP-ribose) polymerase (PARP) inhibitors have emerged as essential therapeutic agents in patients with germline BRCA1/2-mutated BC. A BRCA-like phenotype is displayed by a large subset of patients with germline BRCA1/2-wildtype BC who present with homologous recombination deficiency (HRD). The randomized phase 2 S1416 trial (Rodler et al) evaluated the efficacy of cisplatin combined with the PARP inhibitor veliparib in three cohorts of metastatic BC: mutated germline BRCA1/2, BRCA-like, and non-BRCA–like. A total of 335 patients with metastatic or recurrent triple-negative BC (TNBC) or germline BRCA1/2-mutated metastatic BC were randomly assigned (1:1) to receive cisplatin plus either veliparib or a matching placebo. The findings showed that the addition of veliparib to cisplatin significantly improved progression-free survival (PFS) in patients with BRCA-like metastatic TNBC compared with placebo (5.9 vs 4.2 months; HR 0.57; log-rank P = .01), but not in mutated germline BRCA1/2 (6.2 vs 6.4 months; P = .54) and non-BRCA–like (4.0 vs 3.0 months; P = .57) groups. No new toxicity signals were observed. These findings suggest BRCA-like TNBC might show sensitivity to PARP inhibitors and therefore these agents should be explored further in this cohort.

A recent update from the combined analysis of the SOFT and TEXT studies comparing outcomes in 4690 premenopausal women with estrogen/progesterone receptor–positive early BC (Pagani et al) showed that exemestane plus ovarian function suppression (OFS) led to a greater reduction in recurrence risk compared with tamoxifen plus OFS in premenopausal women. After a median follow-up of 13 years, results showed a 4.6% absolute improvement in 12-year disease-free survival (HR 0.79; P < .001) and a 1.8% absolute improvement in disease recurrence-free interval (HR 0.83; P = .03) with exemestane plus OFS compared with tamoxifen plus OFS. These treatment effects on recurrence began to attenuate over time, being strongest in the first 5 years with no further improvement after 10 or more years. No improvement in overall survival (OS) was noted with exemestane vs tamoxifen, although both arms had excellent survival outcomes (90.1% vs 89.1%; HR 0.93; 95% CI 0.78-1.11). It is important to note that there was a 3.3% absolute improvement in 12-year OS with exemestane plus OFS among patients with HER2-negative tumors who received chemotherapy. This OS benefit was also noted amongst patients with high-risk clinicopathologic characteristics (<35 years and those with > 2 cm or grade 3 tumors), ranging from 4.0% to 5.5% absolute improvement. In conclusion, sustained recurrence risk reductions were noted with adjuvant exemestane plus OFS compared with tamoxifen plus OFS, with the most clinically meaningful survival benefit noted for patients with higher risk tumors. Proper selection of patients who are most likely to benefit from exemestane over tamoxifen is vital to maximize the survival benefit while minimizing the burden of treatment intensification.

Findings from a retrospective study including 221 women with BC who received preoperative neoadjuvant chemotherapy (NAC) showed that the presence of metabolic syndrome (MetS) worsened survival outcomes and increased disease recurrence risk (Zhou et al). Patients were divided into MetS and non-MetS groups according to National Cholesterol Education Program Adult Treatment Panel III criteria to investigate the association between MetS and clinicopathologic characteristics, pathologic complete response (pCR), and long-term survival. The MetS group had a significantly lower likelihood of achieving pCR after NAC compared with the non-MetS group (odds ratio [OR] 0.316; P = .028), with the risk for death (OR 2.587; P = .004) and disease recurrence (OR 2.228; P = .007) being significantly higher in patients with vs without MetS. In a multivariate analysis, MetS (P = 0.028) and hormone receptors status were independent predictors of pCR after NAC in BC. These findings emphasize the importance of timely intervention of metabolic syndrome to improve outcomes in patients with BC.