Henry, N. Lynn

Importance Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the association of endocrine therapy (ET) vs chemotherapy plus endocrine therapy (CET) with CRCI is poorly understood. Objective To compare patient-reported CRCI between women with breast cancer treated with ET vs CET and to consider whether menopausal status may be associated. Design, Settings, and Participants This was a prespecified secondary analysis of RxPONDER (SWOG S1007), a multinational phase 3 randomized clinical trial of more than 5000 women with hormone receptor−positive ERBB2 -negative (formerly HER2 -negative) breast cancer with 1 to 3 involved lymph nodes and Oncotype DX (21-gene recurrence score) of 25 or less. Participants were enrolled from February 2011 to September 2017, with results first reported in December 2020. Participants were randomly assigned to CET or ET, with ongoing follow-up. This secondary analysis assessed cognitive function using the Patient-Reported Outcomes Measurement Information System Perceived Cognitive Function Concerns (PCF) questionnaire at baseline, 6, 12, and 36 months. Data were analyzed from July 2022 to August 2025. Intervention Random assignment to CET or ET. Main Outcomes and Measures Mean PCF standardized (T) scores by menopausal status over time using generalized estimating equations analysis for continuous outcomes. Results Of the 568 patients who completed the baseline questionnaire and were included in the analysis, 139 (24%) were premenopausal (median [range] age, 47.8 [28.0-56.3] years) and 429 (76%) were postmenopausal (median [range] age, 62.3 [37.3-87.6] years). Among the 274 (48%) who received CET and the 294 (52%) who received ET alone, CET was determined to have a greater negative association with patient-reported CRCI in both the pre- and postmenopausal participants during the 36-month follow-up. In the ET alone group, PCF scores for premenopausal participants decreased from baseline to 6 and 12 months (53.53, 51.51, and 51.72, respectively) but recovered to baseline (54.36) at 36 months. For postmenopausal participants, mean PCF scores were essentially stable (51.72, 51.13, 51.11, and 51.70, respectively); however, in the CET group, PCF scores for both pre- and postmenopausal participants decreased from baseline to 6 and 12 months (premenopausal, 52.84, 49.27, 48.04; postmenopausal, 50.65, 48.39, 47.13, respectively) and did not return to baseline at 36 months (premenopausal, 49.25; postmenopausal, 48.44). The difference in longitudinal mean PCF scores over time between CET and ET groups was −3.02 (95% CI, −5.33 to −0.72; P = .01) for premenopausal and −2.37 (95% CI, −3.92 to −0.82; P = .003) for postmenopausal participants. Conclusions and Relevance This secondary analysis of the RxPONDER found that CET had a greater negative association with patient-reported CRCI compared to ET alone in both pre- and postmenopausal participants over a 36-month follow-up period. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of these patients treated with chemotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT01272037

Abstract Purpose Dual HER2 targeting increases pathologic complete response (pCR) rate to neoadjuvant therapy and improves outcomes in both early and metastatic HER2-positive disease. CALGB 40601 is a randomized phase III trial examining the impact of dual HER2 blockade consisting of trastuzumab (H) and lapatinib (L) added to paclitaxel (T) on pCR, considering tumor and microenvironment molecular features. We previously found that pCR was numerically but not significantly increased with dual therapy, and that tumor molecular subtype and evidence of immune activation significantly and independently affected pCR (Carey et al, JCO 2016). In this secondary analysis, we sought to evaluate the effects of treatment arm and gene expression-defined subgroups on invasive disease free survival (IDFS). Patients and Methods Patients (Pts) with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by random assignment with equal probabilityto paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery. A paclitaxel plus lapatinib (TL) arm was closed early based on reports of futility from other trials. A secondary endpoint was IDFS, defined as the time from surgery until local or distant recurrence, new primary, or death from any cause, whichever was first. Gene expression signatures were identified by RNA sequencing. Results Between 12/2008 and 2/2012, 305 pts were enrolled. 261 pts had IDFS and gene expression information available (THL, n = 103; TH, n =101; TL, n = 57); there were no significant differences in clinical characteristics between this subset and the entire population. The median IDFS follow-up was 4.6 years with 40 IDFS events having occurred (THL, n=7; TH, n=19; TL, n=14). IDFS was significantly longer in the THL arm compared to standard TH (HR=0.34; 95% CI: 0.14-0.82; p=0.02). IDFS was also significantly longer among pCR than non-pCR pts (HR=0.40; 95% CI: 0.19-0.81; p=0.01), and did not differ by hormone receptor (HR) status, clinical stage, tumor size, race, menopausal status or age. Among gene expression signatures, only immune activation measured by an IgG signature was associated with longer IDFS (HR=0.71; 95% CI: 0.51-0.98; p=0.04); this signature was previously also associated with pCR. Multivariate analysis showed dual therapy (HR=0.35; p=0.02), pCR (HR=0.36; p=0.01), IgG (HR=0.69; p=0.05), and molecular subtype (LumA vs HER2E, HR=0.24, p=0.005) were associated with longer IDFS. A subgroup analysis by hormone receptor status revealed that among pts with HR+ disease, pts with luminal A experienced longer IDFS (HR=0.23; p=0.02) compared to those with luminal B or HER2-enriched molecular subtypes. Conclusion Dual HER2-targeting with lapatinib added to 16 weeks of TH produced significantly longer IDFS than TH alone, despite modest effects on pCR. Similar to pts with HER2-negative disease, pts with luminal A had better IDFS than those with other molecular subtypes. Immune activation as measured by RNA-based signature independently predicted both pCR and IDFS. Support: U10CA180882, U10CA180821, U24CA196171, P50-CA58823, Susan G Komen, BCRF Citation Format: Krop IE, Hillman D, Polley M-Y, Tanioka M, Parker J, Huebner L, Henry NL, Tolaney SM, Dang C, Harris L, Berry DA, Perou CM, Partridge A, Winer EP, Carey LA. Invasive disease-free survival and gene expression signatures in CALGB (Alliance) 40601, a randomized phase III neoadjuvant trial of dual HER2-targeting with lapatinib added to chemotherapy plus trastuzumab [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-02.

Abstract Background: CYP2D6 is the rate limiting enzyme responsible for the metabolic activation of tamoxifen (tam) to endoxifen. Compared to CYP2D6 poor metabolizers (PM), tam-treated CYP2D6 extensive metabolizers (EM) have higher endoxifen concentrations, more vasomotor symptoms (Goetz, MP J Clin Oncol 2005), and are more likely to discontinue tam (Rae, JM 2009. Pharmacogenomics J). Additionally, higher endoxifen concentrations are associated with a stepwise increase in tam side-effects (Lorizio, W Breast Cancer Res Treat 2012). The data regarding CYP2D6 genotype and recurrence is mixed. Venlafaxine is a weak CYP2D6 inhibitor not known to alter tam pharmacokinetics (PK) and commonly recommended for tam induced hot flashes. We conducted a multicenter pharmacological study to determine whether venlafaxine altered the PK of tam and to determine the distribution of CYP2D6 genotypes in this population Methods: Women taking tam for at least 4 weeks and for whom venlafaxine was recommended for the treatment of hot flashes were eligible. Blood samples were collected prior to and 8–16 weeks following initiation of venlafaxine for steady state tam and metabolites. Genotyping was performed for alleles associated with no (PM; *3, *4, *5,*6); reduced (intermediate, IM; *10, 17 and *41); and ultra-rapid (UM; *1×2) metabolism. Power calculations demonstrated that 17 patients with paired samples were required (two-sided alpha=0.05 t-test, 90% power) to detect a 25% change in endoxifen levels after at least 8 weeks of concurrent treatment. Results: 30 women (median age 48.5) initiated venlafaxine. CYP2D6 genotypes were within Hardy Weinberg Equilibrium (HWE). CYP2D6 UM allele frequency (6.7%) was higher while CYP2D6 *4 (13.3%) was lower than expected compared to an unselected population (0.5 and 21% respectively; Sachse Am. J. Hum. Genet. 1997), resulting in the absence of CYP2D6 PM/PM. Mean (min/max) baseline endoxifen concentrations (8.73; 1.5–20.5 ng/ml) were correlated with CYP2D6 phenotype as follows: intermediate (EM/PM, PM/IM): 6.8 (1.5–11.2); extensive (EM/EM, EM/IM): 9.4 (1.5–20.5) and ultra-rapid (UM/EM: 11.0; 7.8–14) (r2 = 0.35 p = 0.05). In patients with paired samples (n = 20), venlafaxine resulted in a 23% decrease in endoxifen (−2.06 ng/ml; 95% CI −0.69 to −3.04; p = 0.004), but not tam, NDMT, or 4HT concentrations. Following initiation of venlafaxine, CYP2D6 genotype was no longer associated with endoxifen concentrations (r2 = 0.28 p = 0.23). For women with reduced CYP2D6 metabolism [EM/PM (n = 9) or PM/IM (n = 1)], venlafaxine lowered endoxifen concentrations (−2.98 ng/ml) to a level (5.41 ng/ml) reported to be associated with a higher risk of recurrence in adjuvant tam treated patients (Madlensky, L Clin Pharmacol Ther 2011). Conclusions: In this study, women with tam-induced vasomotor symptoms requiring venlafaxine were comprised predominantly of CYP2D6 EM and UM metabolizers. Venlafaxine significantly decreased endoxifen concentrations. Although the optimal concentration of endoxifen is unknown, given prior data linking low endoxifen concentrations with recurrence, venlafaxine should be used with caution in tam treated patients. (Supported by R01CA133049) Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-08.