Evaluation of sensitivity to endocrine herapy index (SET2,3) for response to neoadjuvant endocrine therapy and longer-term breast cancer patient outcomes (Alliance Z1031)

PURPOSE: To evaluate prediction of response and event-free survival (EFS) following neoadjuvant endocrine therapy by SET2,3 index of nonproliferation gene expression related to estrogen and progesterone receptors adjusted for baseline prognosis. EXPERIMENTAL DESIGN: A correlative study was conducted of SET2,3 measured from gene expression profiles of diagnostic tumor (Agilent microarrays) in 379 women with cStage II-III breast cancer from the American College of Surgeons Oncology Group Z1031 neoadjuvant aromatase inhibitor trial SET2,3 was dichotomized using the previously published cutoff. Fisher exact test was used to assess the association between SET2,3 and low proliferation at week 2-4 [Ki67 ≤ 10% or complete cell-cycle arrest (CCCA; Ki67 ≤ 2.7%)] and PEPI-0 rate in cohort B, and the association between SET2,3 and ypStage 0/I in all patients. Cox models were used to assess EFS with respect to SET2,3 excluding cohort B patients who switched to chemotherapy. RESULTS: Patients with high SET2,3 had higher rate of pharmacodynamic response than patients with low SET2,3 (Ki67 ≤ 10% in 88.2% vs. 56.9%, P \u3c 0.0001; CCCA in 50.0% vs. 26.2%, P = 0.0054), but rate of ypStage 0/I (24.0% vs. 20.4%, P = 0.4580) or PEPI = 0 (28.4% vs. 20.6%, P = 0.3419) was not different. Patients with high SET2,3 had longer EFS than patients with low SET2,3 (HR, 0.52, 95% confidence interval: 0.34-0.80; P = 0.0026). CONCLUSIONS: This exploratory analysis of Z1031 data demonstrated a higher rate of pharmacodynamic suppression of proliferation and longer EFS in high SET2,3 disease relative to low SET2,3 disease. The ypStage 0/I rate and PEPI = 0 rate were similar with respect to SET2,3

ERβ-mediated induction of cystatins results in suppression of TGFβ signaling and inhibition of triple-negative breast cancer metastasis.

Triple-negative breast cancer (TNBC) accounts for a disproportionately high number of deaths due to a lack of targeted therapies and an increased likelihood of distant recurrence. Estrogen receptor beta (ERβ), a well-characterized tumor suppressor, is expressed in 30% of TNBCs, and its expression is associated with improved patient outcomes. We demonstrate that therapeutic activation of ERβ elicits potent anticancer effects in TNBC through the induction of a family of secreted proteins known as the cystatins, which function to inhibit canonical TGFβ signaling and suppress metastatic phenotypes both in vitro and in vivo. These data reveal the involvement of cystatins in suppressing breast cancer progression and highlight the value of ERβ-targeted therapies for the treatment of TNBC patients

Physical activity, weight, and outcomes in patients receiving chemotherapy for metastatic breast cancer (C40502/Alliance)

Background: Obesity and inactivity are associated with increased risk of cancer-related and overall mortality in breast cancer, but there are few data in metastatic disease. Methods: Cancer and Leukemia Group B 40502 was a randomized trial of first-line taxane-based chemotherapy for patients with metastatic breast cancer. Height and weight were collected at enrollment. After 299 patients enrolled, the study was amended to assess recreational physical activity (PA) at enrollment using the Nurses\u27 Health Study Exercise Questionnaire. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using stratified Cox modeling (strata included hormone receptor status, prior taxane, bevacizumab use, and treatment arm). All statistical tests were 2-sided. Results: A total of 799 patients were enrolled, and at the time of data lock, median follow-up was 60 months. At enrollment, median age was 56.7 years, 73.1% of participants had hormone receptor-positive cancers, 42.6% had obesity, and 47.6% engaged in less than 3 metabolic equivalents of task (MET) hours of PA per week (\u3c1 hour of moderate PA). Neither baseline body mass index nor PA was statistically significantly associated with PFS or OS, although there was a marginally statistically significant increase in PFS (hazard ratio = 0.83, 95% confidence interval = 0.79 to 1.02; Conclusions: In a trial of first-line chemotherapy for metastatic breast cancer, rates of obesity and inactivity were high. There was no statistically significant relationship between body mass index and outcomes. More information is needed regarding the relationship between PA and outcomes

Evidence-based guidelines for managing patients with primary ER+ HER2− breast cancer deferred from surgery due to the COVID-19 pandemic

Many patients with ER+ HER2- primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER 10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2- breast cancer during and in the aftermath of the COVID-19 crisis

Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers

Resistance to oestrogen-deprivation therapy is common in oestrogen-receptor-positive (ER+) breast cancer. To better understand the contributions of tumour heterogeneity and evolution to resistance, here we perform comprehensive genomic characterization of 22 primary tumours sampled before and after 4 months of neoadjuvant aromatase inhibitor (NAI) treatment. Comparing whole-genome sequencing of tumour/normal pairs from the two time points, with coincident tumour RNA sequencing, reveals widespread spatial and temporal heterogeneity, with marked remodelling of the clonal landscape in response to NAI. Two cases have genomic evidence of two independent tumours, most obviously an ER− ‘collision tumour', which was only detected after NAI treatment of baseline ER+ disease. Many mutations are newly detected or enriched post treatment, including two ligand-binding domain mutations in ESR1. The observed clonal complexity of the ER+ breast cancer genome suggests that precision medicine approaches based on genomic analysis of a single specimen are likely insufficient to capture all clinically significant information

Safety and Feasibility of Minimally Invasive Inguinal Lymph Node Dissection in Patients With Melanoma (SAFE-MILND): Report of a Prospective Multi-institutional Trial.

BACKGROUND: Minimally invasive inguinal lymph node dissection (MILND) is a novel approach to inguinal lymphadenectomy. SAFE-MILND (NCT01500304) is a multicenter, phase I/II clinical trial evaluating the safety and feasibility of MILND for patients with melanoma in a group of surgeons newly adopting the procedure. METHODS: Twelve melanoma surgeons from 10 institutions without any previous MILND experience, enrolled patients into a prospective study after completing specialized training including didactic lectures, participating in a hands-on cadaveric laboratory, and being provided an instructional DVD of the procedure. Complications and adverse postoperative events were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.0. RESULTS: Eighty-seven patients underwent a MILND. Seventy-seven cases (88.5%) were completed via a minimally invasive approach. The median total inguinal lymph nodes pathologically examined (SLN + MILND) was 12.0 (interquartile range 8.0, 14.0). Overall, 71% of patients suffered an adverse event (AE); the majority of these were grades 1 and 2, with 26% of patients experiencing a grade 3 AE. No grade 4 or 5 AEs were observed. CONCLUSIONS: After a structured training program, high-volume melanoma surgeons adopted a novel surgical technique with a lymph node retrieval rate that met or exceeded current oncologic guidelines and published benchmarks, and a favorable morbidity profile

Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance)

To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI)

Loss of Heterozygosity at the CYP2D6 Locus in Breast Cancer: Implications for Germline Pharmacogenetic Studies

Controversy exists regarding the impact of CYP2D6 genotype on tamoxifen responsiveness. We examined loss of heterozygosity (LOH) at the CYP2D6 locus and determined its impact on genotyping error when tumor tissue is used as a DNA source

Functional Genetic Polymorphisms in the Aromatase Gene CYP19 Vary the Response of Breast Cancer Patients to Neoadjuvant Therapy with Aromatase Inhibitors

Aromatase (CYP19) is a critical enzyme for estrogen biosynthesis, and aromatase inhibitors (AIs) are established endocrine therapy for post-menopausal women with breast cancer. DNA samples were obtained from 52 women pre- and post-AI treatment in the neoadjuvant setting. 82 breast cancer and 19 normal breast samples were resequenced to test the hypothesis that single nucleotide polymorphisms (SNPs) in the CYP19 gene might contribute to response to neoadjuvant AI therapy. There were no differences in CYP19 sequence between tumor and germline DNA in the same patient. Forty-eight CYP19 SNPs were identified, with four being novel when compared with previous resequencing data. Genotype-phenotype association studies performed with levels of aromatase activity, estrone, estradiol and tumor size pre- and post-AI treatment indicated that two tightly linked SNPs, rs6493497 and rs7176005 in the 5’-flanking region of CYP19 exon 1.1, were significantly associated with a greater change in aromatase activity after AI treatment. A follow-up study in 200 women with early breast cancer treated with adjuvant anastrozole showed that these same two SNPs were also associated with higher plasma estradiol levels pre- and post-AI treatment. Electrophoretic mobility shift and reporter gene assays confirmed the potential functional effects of these two SNPs on transcription regulation. These studies provide insight into the role of common genetic polymorphisms in CYP19 in variation in response to AIs by breast cancer patients