Progesterone Receptor Positive Breast Cancer Research Articles

Long-Term Adherence to Adjuvant Endocrine Therapy Following Various Radiotherapy Modalities in Hormone Receptor Positive Breast Cancer

Adjuvant endocrine therapy (AET) is standard of care following breast-conserving surgery (BCS) for hormone receptor (HR) positive breast cancer. We compared the rates of long-term AET adherence after various radiation therapy (RT) modalities among patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer treated with BCS.Medical records from patients with stage 0 or stage 1, ER and/or PR positive breast cancer that received adjuvant RT between 2013 and 2015 at a single institution were retrospectively reviewed. We excluded patients with prior breast cancer or ductal carcinoma in situ (DCIS), HR-negative disease, primary tumors > 3cm, involved nodes, and those for whom AET was contraindicated. All patients received BCS followed by adjuvant RT via one of the following modalities: whole breast radiotherapy (WBI), accelerated partial breast irradiation (APBI) with either external beam radiation therapy (EBRT) or fractionated intracavitary high dose rate (HDR) brachytherapy, or single fraction HDR-brachytherapy intraoperative-radiation therapy (IORT) delivered at the time of lumpectomy, on a clinical trial (Precision Breast IORT). Only patients from the completed phase of the protocol were included. All patients were evaluated for up to five years of adherence to AET. Patient and treatment factors were evaluated via a Cox Regression analysis with backward selection of variables based upon P < 0.10 on univariate analysis (UVA) for inclusion in the final model. The Kaplan Meier method was used to model and further evaluate rates of AET adherence based on RT modality and histology as well as among the entire cohort.Ninety-seven patients were eligible for analysis. Thirty patients were treated with WBI, 41 with APBI, and 26 with IORT on clinical trial with a median follow up of 64.2, 72.0, and 58.6 months, respectively. Follow up schedule and evaluation of AET adherence was similar between all groups. For the entire cohort, AET adherence was approximately 67% at 2 years and 58% at 5 years. Among patients in the IORT clinical trial, adherence to AET was 53% at 2 years and 41% at 5 years. In the Cox regression model, histology (DCIS) and RT modality (IORT) were associated with decreased AET adherence at 5 years, with odds ratio (OR) 1.974 (CI: 1.018-3.828, P = 0.044) and OR 2.177 (CI: 1.132-4.186, P = 0.02), respectively.For early stage, HR positive breast cancer, the rate of AET adherence was approximately 58% at 5 years, consistent with prior reports. DCIS histology and receipt of IORT on clinical trial were associated with lower rates of adherence to AET at 5 years. Our findings suggest a potential need for further research aimed at addressing adherence to AET. Additionally, examination of the efficacy of more convenient RT interventions such as APBI and IORT in patients who do not receive AET is warranted.

Is oestrogen receptor-negative/progesterone receptor-positive (ER-/PR+) a real pathological entity?

BackgroundThe existence of oestrogen receptor-negative (ER−)/progesterone receptor-positive (PR+) breast cancer continues to be an area of controversy amongst oncologists and pathologists.MethodsTo re-evaluate breast cancers originally classified as ER−/PR+ via Oncotype DX® assay and compare molecular phenotype with Recurrence Score® (RS) result, clinicopathologic features and clinical outcomes were retrospectively obtained from electronic health records between January 1998 and June 2005. Archived formalin-fixed, paraffin-embedded (FFPE) tumour specimens were tested for the expression of ER, PR and human-epidermal-growth-factor-2. The number of positive ER−/PR+ samples confirmed by transcriptional analysis was the primary outcome of interest with event-free and overall survival as secondary outcomes. Biopsies from 26 patients underwent Oncotype DX testing and analysis.ResultsApproximately 60% were middle-aged (40–50 years old) women, and 84.6% had invasive ductal carcinoma. Based on the Oncotype DX assay, approximately 65% (N = 17) had ER+/PR+ status; 23% (N = 6) had ER−/PR− status; and 12% had a single hormone positive receptor (1 ER–/PR+, 2 ER+/PR–) status. Almost one-quarter of patients were stratified into the low-RS (<18) or intermediate-RS (18–30) results, and half of the patients had a high-RS (>30) result.ConclusionOur findings suggest the ER−/PR+ subtype is not a reproducible entity and emphasises the value of retesting this subtype via molecular methods for appropriate treatment selection and patient outcomes. Multigene assay analysis may serve as a second-line or confirming tool for clinical determination of ER/PR phenotype in breast cancer patients for targeted therapies.

Recurrence score testing does not appear to benefit patients with Grade 1, progesterone receptor-positive breast cancers: An opportunity to eliminate overtreatment and decrease testing costs

BackgroundWe previously described a risk prediction model (Anne Arundel Medical Center [AAMC] model) based on pathology which may eliminate the need for recurrence score (RS) testing in select early-stage breast cancers. There is a concern that patients in discordant risk prediction groups (AAMC vs. RS) may be overtreated or undertreated if RS testing were omitted. MethodsWe queried the Surveillance, Epidemiology, and End Results (SEER) database for all breast cancer patients between 2004 and 2015. AAMC low-risk was defined as Grade 1 and progesterone receptor-positive (PR + ) tumors, while AAMC high-risk was defined as Grade 3 or estrogen-negative tumors. RS low-risk group was defined as RS < 16 and age ≤ 50 years, or RS ≤ 25 and age > 50 years. RS high-risk group was defined as RS > 25. ResultsA total of 71,212 cases were analyzed. Of these, 590 were AAMC low-risk/RS high-risk discordant, while 5,596 were AAMC high-risk/RS low-risk discordant. For AAMC low-risk/RS high-risk discordant, 10-year breast cancer-specific survival (BCSS) did not differ for patients who received adjuvant chemotherapy versus those who did not (93% chemotherapy vs. 99% unknown/no chemotherapy, p = .12). Overall survival (OS) was also comparable (92% chemotherapy vs. 91% unknown/no chemotherapy, p = .42). In the AAMC high-risk/RS low-risk discordant group, 10-year BCSS (92% chemotherapy vs. 96% unknown/no chemotherapy, p = .06) and OS (87% chemotherapy vs. 90% unknown/no chemotherapy, p = .52) did not differ between adjuvant chemotherapy and unknown/no chemotherapy groups. ConclusionsAdjuvant chemotherapy in the AAMC low-risk/RS high-risk and AAMC high-risk/RS low-risk discordant groups did not improve survival. This supports consideration of omission of RS testing in Grade 1, PR + tumors. Patients with Grade 3 tumors do benefit from RS testing.

Phase II clinical trial using anti-CD3 × anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) consolidation therapy for HER2 negative (0–2+) metastatic breast cancer

BackgroundMetastatic human epidermal growth receptor II (HER2) negative breast cancer remains incurable. Our phase I study showed that anti-CD3 × anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) may...

The negative correlation between miR-140-3-p and Metadherin gene in estrogen and progesterone receptor positive–breast cancer

BackgroundBreast cancer is a complicated cancer with different etiologies including both environmental and genetic factors. Aberrant expression of many genes and proteins is essential for its development and progression. Metadherin (MTDH) gene is one of the tumor related genes that involved in tumorigenesis and metastasis. MicroRNAs (miRNAs) are widely involved in cell proliferation, tumor invasion and apoptotic processes. Dysregulation of miRNAs expression was related to carcinogenesis and tumor progression. ObjectiveThis study aimed to assess miR-140-3p expression and its possible target gene MTDH gene expression in breast tumor tissues. Moreover, we aimed to explore the correlation among their expression and different clinicopathological parameters. MethodsBioinformatics analysis was done and revealed that MTDH is a one of many target genes for miR-140-3p. Reverse Transcription-quantitative Real-Time PCR (RT-qPCR) was used to identify the expression level of miR-140-3p and MTDH in 50 breast cancer tissues and 25 normal breast tissues. Results indicated that miR-140-3p was significantly lower in breast cancer tissues than normal breast tissues (P < 0.05). Whereas MTDH expression in breast cancer was higher than in normal tissues (P < 0.05). Moreover, there was a negative association between miR-140-3p and MTDH expression levels. We found that MTDH expression was significantly higher in positive estrogen and progesterone receptors breast cancer tissues as compared to negative tissues. ConclusionThis study highlights on the innovative role of miR-140-3p as new biomarker in breast cancer. The findings reveal the potential role of miR-140-3p in breast cancer pathogenesis and prognosis through targeting MTDH expression. This may give an indication for the emerging effect for miR-140-3p as a new diagnostic and potentially a therapeutic goal in breast cancer.

Cost-effectiveness of endocrine therapy versus radiotherapy versus combined endocrine and radiotherapy for older women with early-stage breast cancer

PurposeTo evaluate the cost-effectiveness of endocrine therapy (ET), radiation therapy (XRT), and combination ET + XRT as post-surgical treatment for older women with early-stage breast cancer from the societal perspective. MethodsWe constructed a Markov state-transition model consisting of three mutually exclusive health-states: Disease-Free, Recurrence, or Death. Osteoporotic fracture, radiation-induced breast fibrosis, and radiation pneumonitis were modeled as treatment-related adverse events (AEs). Cancer registry-linked-Medicare data were used to assess probability of recurrence and total costs, after propensity adjustment to account for treatment selection, among women aged >65 years diagnosed with estrogen receptor positive or progesterone receptor positive (ER+/PR+) breast cancer receiving ET, XRT, or ET + XRT in 2007–2011. Following randomized controlled trials, overall survival was assumed equivalent, but locoregional recurrence varied. Indirect costs and health-state utilities were literature-driven and varied in sensitivity analyses. Costs and outcomes were discounted at 3% annually. ResultsIn a cohort of 10,000 women over ten years, we estimated 1620 total recurrences in the ET-only group, 1296 in the XRT-only group, and 1076 with ET + XRT. Compared to ET-only, the base-case incremental cost-effectiveness ratio (ICER) was $10,826 per quality-adjusted life-year (QALY)-gained for XRT-only and $26,834/QALY-gained for ET + XRT. Similarities in cost and effectiveness between treatments led to highly sensitive results. We also present clinically-relevant patient preference scenarios for recurrence risk-averse patients and near-term AE risk-averse patients. ConclusionsThe cost-effectiveness of regimens including ET and/or XRT in older women with early-stage breast cancer is sensitive to small differences in costs, as well as risk of, and utilities associated with, locoregional recurrence, suggesting that patient preferences concerning treatment benefits and risks should be considered by physicians.

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

BackgroundEpidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.MethodsWe carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.ResultsFor pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8).ConclusionsThe CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

Abstract PO-077: Use of aromatase inhibitors and risk of cardiovascular disease: A population-based study

Abstract Background: Adjuvant endocrine therapy, including aromatase inhibitors (AI) or tamoxifen, is recommended for women diagnosed with estrogen receptor- and/or progesterone receptor-positive breast cancer as it significantly reduces the risk of recurrence and breast cancer-specific mortality. AIs are the preferred treatment for postmenopausal women; however, concerns have been raised with respect to their cardiovascular safety. Some meta-analyses of randomized controlled trials report an increase in cardiovascular disease (CVD) risk with use of AIs compared to tamoxifen; however, “real-world” observational studies have yielded inconsistent findings. Objectives: We aimed to conduct a population-based study in Scotland to investigate whether breast cancer patients treated with AIs are at an increased risk of cardiovascular disease compared to patients treated with tamoxifen. Methods: Women newly diagnosed with breast cancer, from 2009 to 2017, were identified from the Scottish Cancer Registry. AI and tamoxifen use were identified from the nationwide Scottish Prescribing Information System. The primary outcome was CVD, based on incidence or death from CVD obtained from hospital admission and death records, respectively. Cox regression models calculated hazard ratios (HRs) and 95% intervals (CIs) comparing AI use to tamoxifen use and risk of CVD, using an as treated exposure definition. Analyses were adjusted for a range of potential confounders and subgroup analysis investigated risk by CVD subtypes including myocardial infarction, heart failure, ischemic stroke, venous thromboembolism, and angina. Results: The cohort contained 28,712 breast cancer patients, followed for 110,999 person years, during which there were 776 cardiovascular events. Compared to tamoxifen use, AI use was associated with an increased risk of any CVD event (adjusted HR 1.14, 95% CI: 1.02, 1.27), which was particularly marked for ischemic stroke (adjusted HR 1.27, 95% CI: 0.99, 1.63). There were no clear associations for other CVD subtypes. Conclusions: Our preliminary results suggest an increased risk of CVD, and specifically ischemic stroke, in AI users compared to tamoxifen. Additional analyses will be conducted to further investigate these associations, including dose-response. Citation Format: Lauren McVicker, Christopher Cardwell, Úna McMenamin. Use of aromatase inhibitors and risk of cardiovascular disease: A population-based study [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-077.

Personal use of permanent hair dyes and cancer risk and mortality in US women: prospective cohort study

ObjectiveTo evaluate the associations between personal use of permanent hair dyes and cancer risk and mortality.DesignProspective cohort study.Setting and participants117 200 women enrolled in the Nurses’ Health Study, an ongoing...

Association between sociodemographic factors and estrogen receptor-positive, progesterone receptor-positive breast cancer subtypes: A cross-sectional study

Background: The presence of risk factors have a high risk of developing breast cancer. Our study aimed to find an association between sociodemographic factors and the risk of estrogen receptor (ER)-positive, progesterone receptor (PR)-positive breast cancer among women. Methods: A cross-sectional study was conducted on 200 women with breast cancer. Association between sociodemographic factors and hormone receptor subtypes of breast cancer was found using the Chi-square test. Multiple logistic regression analysis was used to know the strong predictors of hormone receptor subtypes. Results: The mean age was 50.08 (10.67) years. Comorbidities had a statistically significant association with ER-positive subtype (p = 0.007). Body mass index had a statistically significant association with PR-positive subtype (p = 0.042). Comorbidities was found to be the strong independent predictor for ER-positive (OR 2.28; 95% CI: 1.28–4.05, p = 0.003) and PR-positive subtypes (OR 1.78; 95% CI: 1.01–3.13, p = 0.03). Conclusion: We conclude that in our study, body mass index was associated with PR-positive subtype, and comorbidities were associated with ER-positive subtype of breast cancer among the women. Comorbidities remained to be a strong independent predictor of ER-positive and PR-positive subtypes of breast cancer.

Toll-like receptor (TLR) gene expression and immunostimulatory effect of CpG oligonucleotides in hormone receptor positive cell line T47D and triple negative breast cancer cell line MDA-MB-468

Background We investigated the expression of TLR genes and the effects of CpG ODN in Estrogen Receptor positive, Progesterone Receptor positive breast cancer cell line (T47D) and a triple-negative breast cancer cell line (MDA-MB-468) followed by studying the immunostimulatory activity of CpG oligonucleotides in breast cancer cell lines T47D and MDA-MB-468. Materials and Methods We evaluated the expression pattern of TLR genes (TLR1 to TLR9) in T47D and MDA-MB-468 cells using Real-time qPCR analysis. The intracellular TLR9 protein expression was studied by flow cytometry. The effect of CpG ODN on cell viability was tested using MTT assay. The relative expression of pro-inflammatory (IL6 and TNFα) and anti- inflammatory/immunosuppressive cytokines genes (IL10 and TGF beta1) were examined by Real-time qPCR. Results We found that MDA-MB-468 cells expressed TLR2, TLR3, TLR6, TLR8, and TLR9 genes and T47D cells expressed TLR3, TRL5, TLR8, and TLR9 genes. Stimulation of TLR9 in vitro with CpG significantly reduced the cell viability of T47D and MDA-MB-468 cells. IL6 cytokine gene expression was significantly reduced in both CpG treated T47D cells and MDA-MB-468 cells. TNFα gene expression was significantly reduced after treatment with CpG in MDA-MB-468 cells but not in T47D cells. IL10 and TGFβ1 expression were downregulated in CpG treated T47D cells. Whereas, IL10 and TGFβ1 were elevated in CpG treated MDA-MB-468 cells. Conclusion Our in vitro finding gives preliminary evidence that triggering TLR9 using CpG ODN decreases the cell proliferation and alters the pro-inflammatory cytokines in favor of inhibition of hormone receptor positive breast cancer cells T47D and triple negative breast cancer cells MDA-MB-468.

Onapristone Extended Release: Safety Evaluation from Phase I-II Studies with an Emphasis on Hepatotoxicity.

IntroductionAntiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure.ObjectiveWe explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I–II studies involving patients with breast, ovarian, endometrial, and prostate cancer.ResultsAmong the 88 patients in two phase I–II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient’s liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist.ConclusionsThese results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.

A prospective study of bone loss in early stage postmenopausal breast cancer treated with aromatase inhibitors

Objective: To investigate the occurrence and development of aromatase inhibitors (AIs) related bone loss in Chinese patients with postmenopausal early-stage breast cancer. Methods: Patients with estrogen receptor (ER) and (or) progesterone receptor(PR) positive postmenopausal early-stage breast cancer who received Letrozole, Anastrozole, or Exemestane as adjuvant therapy were enrolled. Before treatment, baseline bone mineral density (BMD), bone metabolism markers were examined and a lifestyle questionnaire was completed; BMD was examined annually during the treatment; Outpatient visits were conducted to record recurrent and fatal events. Results: From November 2013 to August 2016, 131 patients with breast cancer eligible for enrollment were enrolled. A total of 65 patients had normal baseline bone mass, and 68 patients had reduced bone mass. Letrozole was taken in 69 patients, anastrozole in 52 patients, and exemestane in 10 patients. With a median follow-up of 43.7 months, 100 patients could be evaluated for changes in bone mineral density. Bone mineral density of femoral neck, total hip, and lumbar spine L1 to 4 decreased year by year, and the decrease was the most significant in the first year, which decreased by 2.3%, 2.4%, and 3.9% respectively. Ten new cases of osteoporosis occurred in two years, eight of them occurred in the lumbar spine, all of whom had reduced bone mass at baseline. Among the 131 patients who completed the lifestyle questionnaire, the proportions of daily calcium supplementation and vitamin D were 28.2% and 7.6%, respectively; more than half (52.7%) of them lacked regular exercise. Conclusion: BMD was declining steadily in patients treated with AIs, especially in the first year. Lumbar spine is the most common osteoporosis site, early prevention and health education should be strengthened.

Precautions for Patients Taking Aromatase Inhibitors.

Aromatase inhibitors are the drug of choice for the treatment of estrogen receptor– or progesterone receptor–positive breast cancer in postmenopausal women. Aromatase is an enzyme that catalyzes the final and rate-limiting step in the biosynthesis of estrogen. Inhibitors of this enzyme are an effective therapy for breast cancer. The benefits of these agents have been clearly shown through various clinical trials, yet adherence may be challenging for some patients due to issues of drug interactions, proper first dose education, and adverse effects. Education to prevent and treat adverse effects is of the utmost importance to promote adherence.

Tamoxifen/raloxifene loaded liposomes for oral treatment of breast cancer

Breast cancer is the most common type of cancer and it is the second common cause of cancer-related deaths in women. Hormonal therapy is a quite well-tolerated treatment, for estrogen receptor (ER) and progesterone receptor-positive breast cancers. Selective estrogen receptor modulators (SERM) is a specific drug group, structurally different from estrogen, configured as nonsteroidal estrogen with the ability to bind estrogen receptors competitively. They are not readily soluble in biological fluids and have some bioavailability problems. In this study, liposome formulations of tamoxifen and raloxifene were developed with penetration enhancers dimethyl-β-cyclodextrin (DM-β-CD) or sodium taurocholate (NaTC). These formulations were subjected to in vivo and in vitro tests. Raloxifene and DM-β-CD liposomes showed almost 3.5 folds higher permeability coefficients through Caco-2 cell lines. Tamoxifen DM-β-CD liposomes representing particle size with a value of 244.7 ± 8.1 nm (polydispersity index was 0.332, the zeta potential was −14.8 mV and encapsulation efficiency was 45.1%) have shown higher tumor size reduction (92.5%) and therapeutic efficacy (50%). All these results indicate that SERM drug-containing liposomes with a penetration enhancer can be a better therapeutic alternative for oral treatment of breast cancer.

Abstract P5-12-11: Measuring ovarian escape in pre-menopausal breast cancer patients on ovarian suppression therapy

Abstract Introduction The results of the SOFT and TEXT trials created a paradigm shift in the management of pre-menopausal women with estrogen (ER) or progesterone (PR) receptor positive breast cancer. With findings demonstrating reduced recurrence in high risk patients, the American Society of Clinical Oncology (ASCO) recommended that many in this patient population should receive ovarian suppression (OS) with adjuvant endocrine therapy. However, ancillary analysis of the SOFT trial noted a population of patients with persistently elevated estradiol levels. The clinical significance of this is unknown. The aim of this study was to assess pre-menopausal patients with ER positive breast cancer, in a “real world” clinical setting, who did not achieve maximal estradiol suppression within 3 months, and to evaluate potential contributing risk factors. Methods/Materials This was a single institutional, retrospective, observational study, from February 1, 2010 to January 9, 2018, that evaluated pre-menopausal women receiving adjuvant endocrine therapy with OS (either leuprolide or goserelin). Patients were included if they were receiving adjuvant ovarian suppression with goserelin or leuprolide, had stage I-III ER or PR positive breast cancer, and had at least one estradiol value checked within the first 3 months. The primary objective was to measure the percentage of women with ovarian escape, defined as estradiol level &amp;gt;2.7 pg/mL within 3 months of initiation of OS therapy if on AI therapy, and &amp;gt;21 pg/mL for those patients on tamoxifen. The secondary aim was to associate baseline clinical data (age, body mass index (BMI), and previous receipt of chemotherapy) with higher probability of ovarian escape. Results Between February 1, 2010 and January 9, 2018, 46 patients met inclusion criteria. There were 20 (43.5%) women on tamoxifen and 26 (56.5%) women on an aromatase inhibitor. In the first 3 months, 12 (26.0%) patients failed to achieve maximal OS. Eleven of these continued on OS therapy and 4 (36.3%) did not achieve OS at 6 months. Of these 4 patients who did not achieve ovarian suppression by 6 months, 3 women continued for a total of 12 months, and none of them achieved OS, yielding 6.5% of the total 46 patients who did not achieve ovarian suppression within 1 year. Age was significantly associated with risk of ovarian escape, with older patients (43.0±6.6 years) much more likely to achieve OS within 3 months, compared to younger women (38.5±6.7) (p = 0.037). This difference remained significant in multi-variate analysis. In contrast, BMI, previous chemotherapy, and drug used (leuprolide vs. goserelin) were not significantly associated with likelihood of achieving ovarian suppression. Conclusion It is not uncommon for premenopausal women to have elevated estradiol levels within the first 3 months of ovarian suppression therapy. In this “real world” clinical setting, approximately 1 in 4 women were not maximally suppressed within 3 months. Of these women who did not achieve ovarian suppression in the first 3 months, a quarter of them were also not able to achieve ovarian suppression in the first year. Young age was the most significant risk factor for ovarian escape. Given the relatively high frequency of this phenomenon, larger future studies should evaluate whether ovarian escape in young, pre-menopausal women may be associated with higher recurrence risk, and thus warrant closer monitoring of hormone levels. Table 1: Baseline characteristics by ovarian suppressionAchieved ovarian suppression within 3 monthsp-valueNo (n=11)Yes (n=35)Age38.5±6.743.0±6.60.037BMI29.0±7.627.5±6.50.677Previous Chemotherapy6 (54.6%)21 (60%)1.0Drug0.768Anastrozole3 (27.3%)11 (31.4)Exemestane0 (0%)4 (11.4)Letrozole3 (27.3%)5 (14.3)Tamoxifen5 (45.5%)15 (42.3) Citation Format: Ethan Burns, Susan Xu, Edward McLean, Rosetta Lee, Tejal Patel, Jenny Chang, Polly Niravath. Measuring ovarian escape in pre-menopausal breast cancer patients on ovarian suppression therapy [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 P5-12-11.

Abstract P3-09-07: A multicenter phase Ib/II study for evaluating safety and efficacy of Nivolumab in combination with radiation therapy in patients with HER2-negative metastatic breast cancer (KBCRN-B-002 trial)

Abstract BACKGROUND: In metastatic breast cancer, Overall Response Rate (ORR) for checkpoint inhibitor monotherapy has been limited. Since Radiation Therapy (RT) stimulates anti-cancer immune responses, we evaluated safety and efficacy of a combinatorial therapy of RT with Nivolumab (a Programmed cell death protein 1 (PD-1) inhibitor) on HER2-negative metastatic breast cancer patients in a multicenter and non-randomized phase Ib/II study. PATIENTS AND METHODS: Patients with HER2-negative breast cancer, measurable metastasis (RECIST1.1) and at least one bone metastasis requiring radiation therapy were enrolled. The patients were divided into two cohorts, A and B. Cohort A constitutes estrogen and/or progesterone receptor-positive breast cancer patients that had 1 or 2 lines of endocrine therapy for the metastatic disease. Cohort B constitutes triple negative breast cancer patients that had two or more lines of chemotherapy for metastatic disease and anthracycline and taxane treatment for any disease setting. Single fraction RT of 8 Gy was delivered on day 0. Patients received 3 mg/kg Nivolumab intravenously every 2 weeks from day 1 until the disease progressed. Combined use of endocrine therapy of the physician’s choice was allowed in Cohort A. Primary endpoints were safety and ORR (RECIST1.1) in phase Ib and phase II, respectively. Secondary endpoints were Duration of Response (DOR), Disease Control Rate (DCR) and Progression-Free Survival (PFS). For translational research, we integrated time series multi-omics data that are correlated with Tumor Immune Microenvironment (TIME) to identify novel drug sensitivity-associated signatures using machine learning method. The multi-omics data included data from RNAseq, DNAseq, mass cytometry (CyTOF), multiple cytokines, human leukocyte antigen, radiomics, drug concentrations, tuberculin reaction using Peripheral Blood Mononuclear Cells (PBMCs), serum, plasma, imaging and Formalin-Fixed Paraffin-Embedded (FFPE) samples. RESULTS: 31 patients were enrolled from Jan 2017 to Nov 2018 and 29 patients (18 in Cohort A and 11 in Cohort B) were included in the full analysis set. While seven patients in Cohort A had received 1 or 2 lines of chemotherapy earlier for the metastatic disease, eight patients in Cohort B received three or more lines of chemotherapy. Dose limiting toxicities were not observed in phase Ib. In Cohort A, the ORR was 11.1% (90% with a Confidence Interval (CI) of 3.7-28.6). The best overall responses were: Partial Response (PR) in 2 patients (11.1%), Stable Disease (SD) in 11 patients (61.1%) and Progressive Disease (PD) in 5 patients (27.8%). In Cohort B, ORR was 0% as none of the patients responded to the treatment. The best overall responses were: SD in 4 patients (36.4%), PD in 6 patients (54.5%) and one patient (9.1%) was not evaluated (NE). While the DCR for Cohorts A and B were 72.2% (90% CI: 52.9-85.8) and 36.4% (90% CI: 17.5-60.6), respectively, the median PFS were 4 months (95% CI: 2.1-5.5 months) and 2 months (95% CI: 1.2-4.0 months), respectively. Common toxicities were mild; including 3 patients in Cohort A (16.7%) and 2 patients in Cohort B (18.2%) that experienced grade 3 or 4 toxicity. There were no deaths due to adverse effects. Furthermore, our integrated analysis identified novel candidates for drug sensitivity-associated signatures. CONCLUSIONS: The combination of RT and Nivolumab had a manageable safety profile and demonstrated clinically significant disease control outside the RT fields. Periodic abscopal response data and multi-omics data are also presented. (UMIN: UMIN000026046; ClinicalTrials.gov: NCT03430479). Citation Format: Masahiro Takada, Michio Yoshimura, Kosuke Kawaguchi, Takeshi Kotake, Ryuji Uozumi, Masako Kataoka, Takahiko Koyama, Hironori Kato, Hiroshi Yoshibayashi, Hirofumi Suwa, Wakako Tsuji, Hiroyasu Yamashiro, Tatsuki Kataoka, Hiroshi Ishiguro, Reitaro Tokumasu, Maya Honda, Rikiya Yamashita, Atsushi Yonezawa, Yuki Himoto, Natsuko Onishi, Laxmi Parida, Satoshi Morita, Masakazu Toi. A multicenter phase Ib/II study for evaluating safety and efficacy of Nivolumab in combination with radiation therapy in patients with HER2-negative metastatic breast cancer (KBCRN-B-002 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 P3-09-07.

Progress in endocrine therapy for early breast cancer

Breast cancer is a malignant tumor that occurs in the epithelial tissues of the breast gland. The cause of the disease is not fully understood and may be related to genetic, endocrine and other factors. For estrogen or progesterone receptor-positive early breast cancer, endocrine therapy is efficient, simple, and fewer side-effect, so endocrine therapy plays an important role in the treatment for early breast cancer. But most of them will develop drug-resistant after 8 to 14 months and have to combine with chemotherapy or molecule targeted therapy. However, there are still different ideas in the effects of endocrine therapy drugs alone or in combination with chemotherapy or molecule targeted drugs, pre-menopausally or post-menopausally.

Racial disparities in utilization of gene expression testing in breast cancer patients at an academic medical center.

142 Background: Gene expression profiling of breast cancers, such as the OncotypeDx (ODX) test, PAM 50 and Mammaprint, can define the risk of distant recurrence and assist with decisions about adjuvant chemotherapy. A recent study of all breast cancer patients in Virginia found that only 11.7 % of Caucasian Americans (CA) and 5.1% of African Americans (AA) received genomic testing. Methods: We utilized the Virginia Commonwealth University Health System (VCUHS) Tumor Registry and billing data from 2010-2017 to identify all patients that met the following criteria per NCCN guidelines for genomic testing: early stage (stage I or II) breast cancer, estrogen and/or progesterone receptor positive and lymph node-negative breast cancer. We also obtained records from Genomic Health on ODX testing ordered through VCU Health. Additionally, ODX utilization was stratified by race. We then performed Chi Square analysis. Results: 1080 patients were eligible per NCCN Guidelines. Of these, 248 were eliminated due to having only radiation performed at VCU. 39 were eliminated because initial treatments were at outside hospitals. Of the remaining 793, 536 were CA, 232 AA, 9 Asian and 16 other. Among the patients for whom a genomic test was appropriate, the proportion who actually had such a test performed were: 83.4% for CA, 71.98% for AA, 55.56% for Asians, 81.25 % for Others and 79.7% overall. There was a significant difference between utilization in CAs and AAs (p &lt; 0.001). Conclusions: Breast cancer patients at VCU Health are far more likely to receive gene expression profiling overall compared to the Commonwealth of VA as a whole. This may reflect more equitable and guideline-compliant care in an academic/safety net health system.

BRAF/MEK Pathway is Associated With Breast Cancer in ER-dependent Mode and Improves ER Status-based Cancer Recurrence Prediction

BackgroundAberrant BRAF/MEK signaling was found in nearly 50% of human malignancies and proved to play a critical role in the tumorigenesis of multiple cancers. However, this pathway was relatively seldom studied in breast cancer, and the role of this pathway in the pathogenesis of breast cancer is still controversial. Materials and MethodsBreast cancer gene expression data from The Cancer Genome Atlas (TCGA) and 43 Affymetrix microarray datasets were analyzed. The BRAF/MEK pathway activity was presented with phosphorylated ERK level (for the TCGA dataset) or computed by a gene signature-based algorithm (for Affymetrix datasets). Aberrant activation of BRAF/MEK pathway in breast cancer was assessed in matched normal/tumor tissues. The associations of the BRAF/MEK pathway with clinical outcome in patients with breast cancer were analyzed by logistic regression, Cox regression, and Kaplan-Meier methods. ResultsDown-regulation of the BRAF/MEK pathway was observed in atypical ductal hyperplasia, ductal carcinoma in situ, and invasive breast cancers, with the exception of human epidermal growth factor receptor 2-positive and triple-negative breast cancers. Higher BRAF/MEK pathway activities were associated with better survival in estrogen receptor (ER)-positive (overall hazard ratio [HR], 0.85; P = 5.47E−5; n = 3128) or progesterone receptor-positive (overall HR, 0.85; P = 4.19E−3; n = 1537) breast cancers, but with worse survival in ER-negative (overall HR, 1.13; P = .01; n = 1107) or progesterone receptor-negative (overall HR, 1.13; P = .01; n = 1219) breast cancers. Combination with BRAF/MEK pathway activities could improve ER status-based recurrence prediction for breast cancer. ConclusionBRAF/MEK pathway was associated with the recurrence risk of breast cancer in an ER status-dependent mode. Combination with BRAF/MEK pathway activities could improve the ER status-based recurrence prediction in breast cancer.