ABSTRACT
Introduction: We performed matched case-control studies utilizing cohorts of postmenopausal women with ER+ breast cancer receiving adjuvant aromatase inhibitors (AI) on MA.27 [anastrozole, exemestane] or PreFace [letrozole] to assess the association between estrogen suppression after 6 months of treatment and an early breast cancer (EBC) event within 5 years of AI initiation (Clin Cancer Res 2020;26:2986-98). We found a significant 3.0-fold increase in risk of an EBC event for those taking anastrozole with levels of estrone (E1) >=1.3 pg/mL and estradiol (E2) >=0.5 pg/mL, but not for exemestane or letrozole. Given these findings we designed a prospective pharmacodynamic (PD) study to evaluate the impact of anastrozole (1 mg/day: ANA1) on E1 and E2 levels, and among those with inadequate estrogen suppression (IES: E1 >=1.3 pg/mL and E2 >=0.5 pg/mL), to evaluate the safety and PD efficacy of high-dose anastrozole (10 mg/day: ANA10), which has been found to be safe in prior clinical trials (Cancer 1998;83:1142-52). Method(s): Post-menopausal women with stage I-III, ER >=1% positive/HER2-negative breast cancer who were candidates for anastrozole were eligible after completion of locoregional therapy and chemotherapy, as clinically indicated. Women who were pre-menopausal at diagnosis were not eligible. All patients received 8-10 weeks of ANA1, after which those with adequate estrogen suppression (AES: E1< 1.3 pg/mL or E2< 0.5 pg/mL) came off study. Those with IES went on to receive ANA10 for 8-10 weeks, followed by letrozole (2.5 mg/day: LET) for 8-10 weeks. All patients were managed at their treating oncologist's discretion following study discontinuation. E1 and E2 blood levels were measured pre-treatment and after completion of each treatment cycle by a CLIA-approved liquid chromatography with tandem mass spectrometry in the Immunochemical Core Laboratory at Mayo Clinic. With a sample size of 29 patients with IES after ANA1, a one-sided binomial test of proportions with a significance level of 0.05 will have an 87% chance of rejecting the proportion with AES after ANA10 is at most 25% (Ho) when the true proportion is at least 50%. Specifically, the null hypothesis is rejected if the number of women with AES after ANA10 is 12 or more. Data lock was July 6, 2022. Result(s): Of the 161 women enrolled from April 2020 through May 2022, 3 withdrew consent prior to start of ANA1 and 2 were ineligible;thus, 156 women comprised the study cohort. Median patient age was 64 years (range 44-86), 10% of patients were of Hispanic ethnicity and/or non-white race, and 15% received chemotherapy. Six patients remain on ANA1, and 10 discontinued ANA1 due to refusal (7), adverse event (AE) (2), or COVID-19 (1). Forty-one of the remaining 140 patients (29.3% 95%CI: 21.9- 37.6%) had IES with ANA1. Nine of these 41 patients did not go on to ANA10 due to refusal (6) or AE (3). Of the 32 patients who started ANA10, 8 remain on treatment, 5 discontinued due to refusal (3) or AE (1-grade 2 urinary tract infection;1-grade 1 palpitations), and 19 had a blood draw 45 days or more after starting ANA10. No grade 3-5 AEs or grade 2 hot flashes or arthralgias were reported. Of these 19 patients, 14 achieved AES with ANA10 (73.7% 95%CI: 48.8-90.9%). All 19 patients switched to LET of which 3 remain on treatment, 1 is missing E1/E2 data, and 15 had a blood draw 45 days or more after starting LET. Of these 15 patients, 10 maintained AES, 2 acquired AES with LET, and 3 no longer had AES. Anastrozole and letrozole drug levels will be reported at the meeting. Conclusion(s): Approximately 29% of postmenopausal women with ER+/HER2- BC receiving adjuvant anastrozole 1 mg/daily had IES. A majority of these patients achieved AES with dose escalation to ANA10 without tolerability issues. E1 and E2 levels are logical biomarkers given the mechanism of action of anastrozole, and further study utilizing them to determine the optimal dose of anastrozole for a given patient should be performed.
ABSTRACT
The value of genetic counseling and testing to cancer prevention, early detection, and treatment options to ensure optimal outcomes is widely acknowledged by providers, payers and patients. However, many individuals who should receive genetic counseling are never offered this service. All patients with early onset (<=age 45), triple negative (<=60) and metastatic HER2 negative breast cancer should be offered genetic counseling and testing (GC/GT) per National Comprehensive Cancer Network guidelines. A quality improvement project to actively identify and offer genetic counseling to all women with early onset, triple negative and metastatic breast cancer was implemented. Baseline information on the number of early onset (<=45), triple negative and metastatic HER2 negative breast cancers diagnosed January 2018-June 2019 was collected and cross-referenced with the Cancer Genetics Risk Assessment patient database and the electronic health record (EHR) to see how many had GC/GT in our department or the breast surgeons' office. We developed questions for an electronic screening tool used by the navigation team when meeting with patients for the first time, screening for personal or family history criteria that would flag patients at increased risk for hereditary cancer. If any questions were flagged, the patient was asked by the navigator if they would be interested in a genetic counseling appointment to consider genetic Stesting. Training was provided to the navigation team so that they could answer basic questions, biweekly meetings were set up to discuss patients, and a flier and informational videos were made available to patients who wanted more information about GC/GT. If a patient was agreeable to genetic counseling, an automated email was triggered to the genetics team, who contacted the patient for an appointment. A standing order was obtained from willing breast surgeons and oncologists within our network to streamline the referral process. In the 18-month baseline period, there were 126 patients diagnosed with early onset, 36 with triple negative <=60 and 30 with metastatic HER2 negative breast cancer. Of these, 57.1% of early onset, 66.7% triple negative and 3.3% of those with metastatic breast cancer had documentation of GC/GT. A paper screening tool was implemented in July 2019 with implementation of an electronic version in November 2019. In the 18-month intervention period, there were 100 patients diagnosed with early onset, 39 with triple negative and 22 patients with metastatic breast cancer. Of these, 86% of early onset, 87.2% of triple negative and 31.8% of metastatic breast cancer patients had documented GC/GT.A limitation of this project is that some patients leave the system to be treated elsewhere after diagnosis and some may have been tested in their private practitioner's office that does not connect with our EHR. Additionally, some may have been offered GC/GT but declined or were unwilling/unable to complete an appointment. Finally, the pandemic likely had an impact on this project, since fewer women were undergoing mammography screening due to COVID-19 restrictions, resulting in fewer diagnoses of breast cancer. By leveraging the navigation team's interaction with breast cancer patients, we were able to improve identification and referral of more patients with early onset, triple negative <=60 and metastatic HER2 negative breast cancer for GC/GT. One barrier to genetic counseling that has been previously identified is a lack of physician referral. Active engagement with a breast navigator can circumvent this barrier. De-identified aggregate data from this quality improvement project was shared with the Association for Community Cancer Centers as part of a larger project, supported by a grant from Pfizer.