Pieńkowski, Tadeusz

Abstract Purpose: Cardiac toxicity is a serious potential complication of HER2-directed therapies and anthracyclines. HER2 codon 655 and SLC28A3 gene polymorphisms have been reported to be associated with cardiac toxicity from anti-HER2 and anthracycline therapy, respectively. Association of the polymorphism at HER2 codon 655 with prognosis has also been reported. Experimental Design: Whole blood samples from patients treated on a randomized adjuvant breast cancer trial (BCIRG-006) that compared chemotherapy with or without trastuzumab plus either anthracycline or nonanthracycline chemotherapy were tested for genetic polymorphisms in HER2 codon 655 and SLC28A3. Genotypes were correlated with cardiac function and disease-free survival (DFS) outcomes. Results: Of 3,222 patients enrolled in BCIRG-006, 662 patient samples were successfully genotyped for the rs1136201 allele in HER2 (codon 655): 424 (64%) were AA, 30 (4.5%) were GG, and 208 (31%) were AG genotype. In addition, 665 patient samples were successfully genotyped for the rs7853758 allele in the SLC28A3 gene: 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. Follow-up time was 10 years. No correlation between DFS, cardiac event rate, or mean left ventricular ejection fraction (LVEF) and rs1136201 genotype was seen in the trastuzumab-treated or non–trastuzumab-treated patients. Moreover, mean LVEF and cardiac event rates were similar in all rs7853758 genotype groups treated with anthracycline-based therapy. Conclusions: In the largest study to date to evaluate whether two polymorphisms are associated with DFS and/or cardiac toxicity in HER2-positive breast cancer treated with trastuzumab and/or anthracyclines, we observed no correlation.

Abstract Introduction: Although HER2+ breast cancer (BC) is considered a moderately immunogenic tumor, several studies have shown a role of pre-existing immunity associated with favorable long-term prognosis and better response to treatment. In this study, we performed exploratory analyses to assess whether the efficacy of HER2 targeted treatment in the MARIANNE trial correlated with immune gene expression. Methods: MARIANNE (NCT01120184) is a phase 3 study in patients (pts) with centrally confirmed HER2+ local advanced/metastatic BC naïve to prior treatments in the advanced disease. Pts were randomized (1:1:1) to trastuzumab+taxane (HT), T-DM1, or T-DM1+Petuzumab (P) and the trial showed noninferior PFS of T-DM1 and T-DM1+P vs HT. Gene expression (RNA) analysis was performed on tumor samples by a custom 800-gene codeset on the nCounter platform. PD-L1, CD8 expressions and immune gene signatures (sign) analyses were assessed by multivariate Cox regression models using median (cut-off) as categorical variable and adjusted by prior HT, presence of visceral disease, world region, baseline ECOG, measureable disease at baseline, therapy setting, HER2 mRNA expression, PIK3CA mutation status. Results: MARIANNE randomized 1095 pts (HT, n=365; T-DM1, n=367; T-DM1+P, n=363). Gene expression results were available for 671 pts (61.3% of the intent-to-treat [ITT] population) which was representative of ITT. In ITT, HR below 1 was observed when comparing pts with high (>median) vs low (≤median) immune gene expression by clinical outcome suggesting a potential association of high immune marker expression with improved PFS (Table 1) and to some extent with OS (data not shown). This association was primarily observed in the T-DM1 arm where the HR suggested a risk reduction of disease progression(PD)/death especially in the high Teff, high PD-L1 and high CD8 subgroups, and to some extent in the HT arm (Table 1). When assessing the predictive impact on PFS by comparing T-DM1 vs HT, HR below 1 was observed especially in pts with high Teff signature, high PD-L1 and high CD8 expressions (HR 0.67 (95% CI (0.47-0.95)), HR 0.68 (95% CI (0.48-0.97), and HR 0.64 (95%CI 0.44-0.93), respectively). When comparing T-DM1+P vs. HT, HR below 1 was observed especially in pts with low Teff signature and low PD-L1 expression (HR 0.70 (95% CI (0.50-0.99), and HR 0.68 (95% CI (0.48-0.96) respectively). No clear differences between immune gene expression subgroups was observed when comparing treatment arms in regards to OS (data not shown). Conclusions: In the exploratory analysis from the MARIANNE study, high immune gene expression, especially in the high PD-L1, CD8 and Teff subgroups, showed an association with improved clinical benefit with HRs reflecting for a risk reduction of PD/death for PFS and partially for OS. This association was less obvious in the T-DM1+P arm. When comparing the treatments effect, the data showed a potential impact of high Teff signature, and high CD8 and PD-L1 expressions on T-DM1 and less on HT. The potential opposite association of low Teff signature and low PD-L1 expression with improved benefit in the T-DM1+P arm was unexpected and needs further investigation. Table 1: Prognostic biomarker effect on PFSBiomarker by categories (>Median vs ≤Median)HR (95% CI) ITT n=671HR (95% CI) HT n=220HR (95% CI) T-DM1 n=227HR (95% CI) T-DM1+P n=224Teff sign0.89 (0.73-1.09)0.97 (0.68-1.38)0.64 (0.45-0.91)1.09 (0.75-1.58)Th1 cytokine sign0.91 (0.74-1.11)0.92 (0.64-1.31)0.78 (0.55-1.11)0.96 (0.67-1.36)Checkpoint inhibitor sign0.95 (0.78-1.15)0.91 (0.64-1.29)0.90 (0.64-1.26)1.02 (0.71-1.47)PD-L10.80 (0.66-0.98)0.79 (0.55-1.13)0.62 (0.44-0.87)1.07 (0.74-1.55)CD80.91 (0.75-1.11)1.10 (0.77-1.57)0.66 (0.46-0.93)0.98 (0.68-1.41) Citation Format: Edith A Perez, Sanne Lysbet de Haas, Carlos H Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pier Franco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier B Pivot, Howard A Burris III, Chiara Lambertini, Silke Hoersch, Monika Patre, Paul Anthony Ellis. Association of immune gene expression with outcome in the MARIANNE phase 3 clinical trial in HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-11.

Background In the phase 3 MARIANNE trial, trastuzumab emtansine (T‐DM1) with or without pertuzumab showed noninferior progression‐free survival and better tolerability than trastuzumab plus a taxane (HT) for the first‐line treatment of human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient‐reported outcomes and biomarker analyses. Methods OS was assessed in 1095 patients with HER2‐positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T‐DM1 plus a placebo (hereafter T‐DM1), or T‐DM1 plus pertuzumab (T‐DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted. Results The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T‐DM1, and T‐DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T‐DM1 (64.4 months) and T‐DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T‐DM1 (47.1%) or T‐DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3‐point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T‐DM1+pertuzumab (4.2 months) than T‐DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T‐DM1 arm. Conclusions These results support T‐DM1 as a first‐line treatment for patients with HER2‐positive metastatic breast cancer who are deemed unsuitable for taxane‐based therapy.

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) –targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.

Abstract Introduction: Small studies have indicated a possible correlation between a HER2 gene polymorphism at codon 655 and trastuzumab-associated cardiotoxicity. Association between a synonymous coding variant rs7853758 within the SLC28A3 gene and anthracycline induced cardiotoxicity has also been reported. This study aimed to validate these correlations and assess for any relationship with prognosis. Methods: Genomic DNA was isolated from 666 patients enrolled in a large trial of adjuvant chemotherapy in HER2 amplified early breast cancer (BCIRG 006). Genotyping was conducted using Sequenom MassARRAY System for HER2 G->A polymorphism at amino acid codon 655 (rs1136201) and variant rs7853758 (L461L) within the SLC28A3 gene. Results: Of the 666 patients analyzed, 216 patients were treated with anthracycline based therapy, 226 with trastuzumab based therapy, and 224 with regimens containing both an anthracycline and trastuzumab. Compared with the overall results of the BCIRG006 study (N=3,222), in the subset of patients genotyped in this analysis, a less robust improvement in disease free survival (DFS) was observed for the trastuzumab arms than control arm (HR, 0.821). When stratified for prognostic features, the hazard ratio in favor of trastuzumab was consistent with that of the overall study (HR, 0.674). Samples from 662 patients were successfully genotyped for rs1136201. Of these, 424 (64%) were AA, 30 (4.5%) were GG, 208 (31%) were AG genotype. Samples from 665 patients were successfully genotyped for rs7853758. Of these, 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. There was no correlation seen between mean left ventricular ejection fraction (LVEF) and HER2 genotype at codon 655 in patients treated with trastuzumab. Of patients tested for the HER2 polymorphism, cardiac dysfunction [defined as > 10% decline in LVEF or clinical congestive heart failure (CHF)] developed in 16% of patients with AA, 17% of patients with GG and 20% of patients with AG. There was also no correlation between mean LVEF and variant rs7853758 in patients treated with anthracyclines. The percentage of patients who developed cardiac dysfunction was 13%, 17% and 21% in AA, GG, and AG genotypes respectively. No correlation between disease free survival and any of the genotypes was seen. Conclusion: In the largest analysis to date to evaluate for relationship between cardiac toxicity and HER2 polymorphism, we did not find a correlation with rs1136201 HER2 polymorphism and trastuzumab induced cardiac toxicity. Our study also did not show a correlation between variant rs7853758 (L461L) and anthracycline induced cardiotoxicity. Neither polymorphism correlated with prognosis. Citation Format: Peddi PF, Hurvitz SA, Fasching PA, Wang L, Cunningham J, Weinshilboum RM, Liu D, Quinaux E, Fourmanoir H, Robert NJ, Valero V, Crown J, Falkson C, Brufsky A, Pienkowski T, Eiermann W, Martin M, Bee V, Slamon DJ. Genetic polymorphism and correlation with treatment induced cardiotoxicity and prognosis in HER2 amplified early breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-09.

Abstract Up to one fourth of women diagnosed with early breast cancer (EBC) have tumors that are human epidermal growth factor receptor 2 (HER-2) positive. This is associated with a high risk of relapse and death from meta-static disease. Trastuzumab, a monoclonal antibody directed against the extracellular domain of HER-2, improves survival and quality of life in women with HER-2-positive metastatic breast cancer receiving chemotherapy. Four major adjuvant trials—Herceptin® Adjuvant (HERA), National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group (NCCTG) N9831, and Breast Cancer International Research Group (BCIRG) 006—including between them >13,000 women with HER-2-positive EBC, have investigated different adjuvant treatment approaches with trastuzumab. These trials have shown that trastuzumab reduces the 3-year risk of recurrence by about half in this population. The benefit was similar across the trials despite differences in patient populations, chemotherapy regimens, and sequencing of treatment. At a 2-year follow-up, interim results from the combined analysis of the NSABP B-31 and NCCTG N9831 trials showed a one third lower mortality for trastuzumab, and there was a trend toward an overall survival benefit in the HERA and BCIRG trials. A small Finnish trial, FinHer, investigating another regimen of trastuzumab, has also shown similarly positive results. Further follow-up of the major adjuvant trials will clarify the survival benefit for women receiving trastuzumab, as well as the optimal treatment duration (1 or 2 years). Notably, cardiac events in the trastuzumab-containing arms of these trials have remained within acceptable levels, with a slightly higher (0.6%–3.3%) incidence of congestive heart failure that mostly responded to treatment. Further follow-up will provide information on long-term cardiac safety. Overall, results from clinical trials are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER-2-positive EBC based on the risk:benefit ratio demonstrated in these studies.