Citations

Abstract Introduction: Paclitaxel induced peripheral neuropathy (TIPN) is one of the most important survivorship issues of cancer patients with the potential to substantially impact quality of life. TIPN can lead to dose reductions, early cessation, and has the potential to compromise treatment efficacy. We previously reported both rare (SBF2) and common germline (FCAMR) predictors for TIPN in patients of African descent through whole-exome sequencing (WES) and a genome-wide association study (GWAS), respectively, in the adjuvant, randomized phase III breast cancer trial, E5103. These predictors are now being evaluated in the prospective ECOG-ACRIN trial EAZ171 (NCT04001829). We have also previously reported our evaluation of common germline variants for patients of European descent through GWAS in E5103 with validation in another adjuvant breast cancer trial, E1199. Herein, we evaluated for rare variants that were associated with risk of TIPN in patients of European ancestry from WES in E5103. Methods: Gene-based rare variant analyses using SKAT were performed to compare select cases of severe TIPN (n=172) and controls without any evidence of TIPN (n=170) derived from E5103. Cases were defined as those with at least grade 3 TIPN and controls were optimally. matched by demographic and risk factors and had no reported evidence for TIPN of any grade. Germline WES was conducted using Ion Proton™ Sequencers from Life Technologies with an average >100X coverage of the exome. Rare variants with a minor allele frequency <3% predicted to be deleterious by protein prediction programs were retained for the analysis. 7,278 genes passed quality control and were included in the analysis, setting the threshold for significance at a p-value < 6.87 ×10-6 after Bonferroni correction. Results: Cytochrome P450 oxidoreductase (POR) was significantly associated with an increased risk of grade 3+ TIPN (p =1.82 ×10-6). Six variants predicted to be deleterious in POR were identified in the study population. Paclitaxel is predominately metabolized by cytochrome P450 (CYP) 2C8 and 3A4. A functional cytochrome P450 oxidoreductase is required for the catalytic activities of all 57 CYP family members to metabolize drugs, xenobiotics, and steroid hormones. Conclusion: Rare variants in cytochrome P450 oxidoreductase predicted an increased risk of severe TIPN in patients receiving paclitaxel. These rare variants in POR may modulate the catalytic activities of P450 enzymes that are responsible for paclitaxel metabolism and have a striking biological rationale as contributors to TIPN. Work is ongoing to validate these findings mechanistically and to identify strategies to nullify the impact of these deleterious variants. Citation Format: Fei Shen, Guanglong Jiang, Laura Gardner, Gloria Xue, Santosh Philips, Reynold Ly, Osei Wilberforce, Xi Wu, Erica Cantor, Chau Dang, Donald Northfelt, Todd Skaar, Kathy D. Miller, George Sledge, Bryan P Schneider. Cytochrome P450 reductase gene, POR, associated with paclitaxel induced peripheral neuropathy in patients of European ancestry from the adjuvant breast cancer trial, ECOG-ACRIN E5103 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-02.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

PURPOSE The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2–positive (HER2+) breast cancer (BC). METHODS Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m 2 IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1. RESULTS The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH ( P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis ( P < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH. CONCLUSION Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH.

520 Background: Systemic inflammation may contribute to cancer progression (PMC2803035), including recurrence of early breast cancer (PMC4828958). We hypothesized that inflammatory cytokines and/or chemokines may be associated with distant recurrence (DR). Methods: We performed a case:control study in women with stage II-III Her2-negative breast cancer, all of whom had surgery and adjuvant chemotherapy (doxorubicin/cyclophosphamide, then weekly paclitaxel) with/without bevacizumab, plus endocrine therapy if ER-positive (PMC6118403). Propensity score matching was used to identify approximately 250 case:control pairs (with/without DR). Serum samples obtained before adjuvant chemotherapy were analyzed using the MSD V-Plex Human Cytokine 36-Plex Kit for detection of human cytokines and chemokines involved in the Th1/Th2 pathway, chemotaxis, the Th17 pathway, angiogenesis, and immune system regulation. Conditional logistic regression analysis, with models fit via maximum likelihood, were used to estimate hazard ratios (HRs) and test for associations. Due to skewed nature of cytokines, HRs are reported on log base 2 scale. If adjusted for multiple testing including 36 markers, a p value of < 0.0014 would be required for statistical significance. Results: A total 249 matched pairs (498 patients) were identified. Covariates used for propensity score matching included age, menopausal status (post 54% vs. pre/peri 46%), ER/PR status (one/both pos 64% vs. both neg 36%) tumor size ( < = 2cm 17%, > 2-5cm 67%, > 5cm 16%) nodal status (neg 15%,1-3+ 32%, 4+ 53%), and grade (low 3%, int. 31%, high 66%). The only biomarker associated with a significantly increased DR risk when adjusted for multiple testing was the proinflammatory cytokine IL-6 (HR 1.37, 95% confidence intervals [CI] 1.15, 1.65, p = 0.0006). Others associated with a 2-sided p value < 0.05 included the chemokine MDC(macrophage-derived chemokine/CCL22) (1.90, 95% CI 1.17, 3.1, p = 0.0098), the T helper cell inflammatory cytokine IL-17A (HR 1.36, 95% CI 1.10, 1.67, p = 0.0052), and the cytokine VEGF-A (HR 1.13 for, 95% CI 1.01, 1.27, p = 0.037). There was no statistical interaction between VEGF-A and bevacizumab benefit. The median and mean value for IL-6 was 0.95 and 7.5 pg/ml (range 0.04-2761.24 pg/ml). Conclusions: This analysis provides level 1B evidence indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher DR risk in high-risk stage II-III breast cancer despite optimal adjuvant systemic therapy. This provides a foundation for confirmatory validation of IL-6 as a prognostic biomarker, and potentially as a predictive biomarker for testing therapeutic interventions targeting the IL-6/JAK/STAT3 pathway. Supported by NCI U10CA180820,180794,180821; UG1CA189859,232760,233290, 233196; Komen Foundation; Breast Cancer Research Foundation. Clinical trial information: NCT00433511.

PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) –targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival. PATIENTS AND METHODS Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples. RESULTS One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS. CONCLUSION In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

Abstract Background: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI&lt;3040/52 (77%)63-87%6/16 (38%)15-65%30+6/9 (67%)30-93%3/4 (75%)19-99%Endocrine therapy currentlyYes27/39 (69%)52-83%2/12 (17%)2-48%No19/22 (86%)65-97%7/9 (78%)40-97% Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial) [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 P2-13-02.

9508 Background: Chemotherapy-related amenorrhea (CRA) is associated with infertility and may impact treatment decision-making. We investigated whether anti-mullerian hormone (AMH) levels before chemotherapy predict likelihood of CRA. Methods: 591 patients enrolled on the quality of life substudy of ECOG5103, which randomized breast cancer patients to doxorubicin-cyclophosphamide followed by paclitaxel: 1) alone; 2) with concurrent bevacizumab; or 3) with prolonged bevacizumab. 144 of the 195 women who reported a period <12 months before enrollment consented to serum collection prior to chemotherapy. AMH was measured in 143 with available serum. Participants self-reported menstrual frequency at 12 and 18 months after enrollment. 12-month CRA was defined as no menses for 6 months before the 12-month survey, and 18-month CRA as no menses for 6 months before the 18-month survey. Fisher’s exact test was used to identify associations with CRA. Results: Of the 143, 16 were excluded due to bilateral oophorectomy or initiation of ovarian function suppression within 12 months, and 2 due to missing data at 12 months. In the remaining 125, median age at enrollment was 45 (range 25-55). 103 (82%) had CRA at 12 months, including 68% of patients </= 45 (43/63) and 97% of patients >45 (60/62). Median pre-chemotherapy AMH was 0.11 (range 0.01-8.63). 12-month CRA was more likely in women who received bevacizumab (p<0.01), were >45 (p<0.01), and had AMH </=0.11 (p<0.01) pre-treatment. Hormonal tx was not associated with 12-month CRA (p=0.63). 100 patients were eligible for 18-month CRA analysis: 81 (81%) had CRA, including 63% of patients </= 45 (33/52) and 100% (48/48) of patients >45. 18-month CRA was more likely in women >45 (p<0.01) and with AMH </=0.11 (p<0.01) pre-treatment. Bevacizumab (p=0.15) and hormonal tx (p=0.07) were not statistically significant predictors of 18-month CRA. Conclusions: Pre-chemotherapy AMH predicts risk of CRA at 12 and 18 months, and is a promising biomarker of ovarian reserve in young breast cancer survivors. Longer studies will be needed to ascertain whether lower pre-treatment AMH is associated with increased risk of later infertility. Clinical trial information: NCT00433511.

6025 Background: Blinding patients to treatment regimen is an important component of high quality randomized clinical trials although concern exists about how receipt of a placebo will impact participants’ views. In ECOG5103, patients were randomized to receive adjuvant chemotherapy for breast cancer with either placebo (arm A) or bevacizumab (arms B and C) and treatment assignment was unblinded by 24 weeks. We sought to determine if unblinding was associated with differential changes in participants’ views. Methods: The Decision-Making/Quality of Life component (DM-QOL) included all patients enrolling on E5103 between 1/5- 6/8/10. Women were surveyed pretreatment and after unblinding. Wilcoxon rank sum testing was used to examine differences. Results: 572 patients on DM-QOL started protocol therapy; 118 on arm A, 454 on arm B/C; the two groups (arm A vs. B/C) were well balanced. 516 patients participated in pretreatment, 514 in unblinding survey. Pretreatment, 32% reported >moderate chance of recurrence in 5 years, 27% >moderate chance of serious problem from treatment, 99% feeling at least somewhat informed, 98% at least somewhat confident in study participation, most “extremely” confident. Overall, median response scores did not change over time, with no statistically significant differences between the groups in changes in perceptions of: recurrence risk (p=0.45); chances of a serious problem (p=0.12), feeling informed (p=0.99). However, they differed in confidence about study participation (p=0.04): after unblinding, a higher % of placebo-treated patients had increased confidence (38% vs. 25%), and a higher % of bevacizumab-treated patients had decreased confidence (29% vs. 22%), although 44% across all arms had no change. Conclusions: In a placebo-controlled, double-blinded RCT, unblinding did not significantly affect most participants’ views, regardless of receipt of placebo or experimental drug. However, confidence in study participation may have been affected by knowledge of receipt of bevacizumab; publicity surrounding this experimental therapy may have affected results.