Triple-negative breast cancer (TNBC) is a heterogeneous disease in which tumors are defined by lack of expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human ...epidermal growth factor receptor 2 (HER2) receptor. No targeted therapies are available for the treatment of TNBC, and chemotherapy remains the standard of care. Gene expression profiling has identified six distinct molecular subtypes of TNBC. The identification of novel targets, coupled with the development of therapies for different subsets of TNBC, holds great promise for the future treatment of this aggressive form of breast cancer. This review focuses on novel therapies in development for the treatment of TNBC.
Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) ...and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women.
Abstract Given high costs of Oncotype DX (ODX) testing, widely used in recurrence risk assessment for early-stage breast cancer, studies have predicted ODX using quantitative clinicopathologic ...variables. However, such models have incorporated only small cohorts. Using a cohort of patients from the National Cancer Database (NCDB, n = 53,346), we trained machine learning models to predict low-risk (0-25) or high-risk (26-100) ODX using quantitative estrogen receptor (ER)/progesterone receptor (PR)/Ki-67 status, quantitative ER/PR status alone, and no quantitative features. Models were externally validated on a diverse cohort of 970 patients (median follow-up 55 months) for accuracy in ODX prediction and recurrence. Comparing the area under the receiver operating characteristic curve (AUROC) in a held-out set from NCDB, models incorporating quantitative ER/PR (AUROC 0.78, 95% CI 0.77–0.80) and ER/PR/Ki-67 (AUROC 0.81, 95% CI 0.80–0.83) outperformed the non-quantitative model (AUROC 0.70, 95% CI 0.68–0.72). These results were preserved in the validation cohort, where the ER/PR/Ki-67 model (AUROC 0.87, 95% CI 0.81–0.93, p = 0.009) and the ER/PR model (AUROC 0.86, 95% CI 0.80–0.92, p = 0.031) significantly outperformed the non-quantitative model (AUROC 0.80, 95% CI 0.73–0.87). Using a high-sensitivity rule-out threshold, the non-quantitative, quantitative ER/PR and ER/PR/Ki-67 models identified 35%, 30% and 43% of patients as low-risk in the validation cohort. Of these low-risk patients, fewer than 3% had a recurrence at 5 years. These models may help identify patients who can forgo genomic testing and initiate endocrine therapy alone. An online calculator is provided for further study.
191
Background: Patients with early stage breast cancer commonly receive anthracycline and anti-Her2 directed therapies which can result in cardiotoxicity, making cardiac monitoring crucial. In 2018, ...our rate of obtaining a follow up echocardiogram in this patient population was 38%. Subsequently, use of myocardial strain imaging in conjunction with echocardiography became available at our institution, allowing for potential earlier detection of cardiac dysfunction. We aimed to increase utilization of strain imaging and rate of follow up echocardiogram monitoring to at least 50% in hopes of enhancing prevention efforts. Methods: We developed a standardized protocol for cardiac monitoring in patients receiving cardiotoxic chemotherapy. We provided education to staff and workflow modification to include standard orders for strain echocardiogram in all relevant chemotherapy plans. Chart review for Stage 1-3 breast cancer patients who received anthracycline or trastuzumab based therapy at our ambulatory cancer center from January 2019 to December 2021 was performed. Completion of follow up echocardiogram and rate of strain imaging before and after July 2020 was assessed, as this is when strain imaging became widely available. Results: Rates of obtaining baseline echocardiogram were excellent. Rates of strain echocardiogram use improved from 26.3% to 97.9% following July 2020. Follow up echocardiograms were obtained regularly in those receiving trastuzumab based therapy before and after July 2020 at rates of 91.8% and 87.5%. Rates of follow up echocardiograms in those receiving anthracycline-based therapy also improved to our goal of greater than 50%, but was lower than the trastuzumab group at 57%. However, assessment of follow up cardiac imaging in the 2021 treatment group is still ongoing. Conclusions: We successfully implemented a program to standardize cardiac monitoring in patients undergoing cardiotoxic chemotherapy for breast cancer at our institution. We anticipate this will enhance detection of cardiotoxicity and utilization of consultative cardio-oncology services. Additional efforts to improve follow up cardiac imaging through collaboration with our survivorship program are ongoing.Table: see text
1095
Background: Metastatic breast cancer is incurable, and novel treatment (tx) strategies are needed. Single agent immune checkpoint inhibitor (ICI) tx has limited efficacy; combination approaches ...may yield better results. Multiple mechanisms of glucocorticoid-induced immunosuppression have been proposed, including the suppression of the cytotoxic Th1 cytokine response via glucocorticoid receptor (GR) activation. We hypothesize that pretreatment with a GR antagonist shifts the cytotoxic immune response toward Th1, thus enhancing response to ICIs. We present the safety and efficacy of the combination of pembrolizumab and mifepristone in advanced HER2-negative breast cancer. Methods: This (NCT03225547) was a phase II non-randomized study of pembrolizumab and mifepristone in patients (pts) with advanced HER2-negative breast cancer. Pts with prior ICI tx were excluded. Pts received mifepristone 300mg daily and pembrolizumab 200mg every 3 weeks; mifepristone was started 7 days prior to pembrolizumab. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety and tolerability. Results: 18 patients were enrolled from March 2018 – November 2020; 10 patients with TNBC (cohort 1) and 8 patients with HR+ BC (cohort 2). Mean age was 53 yrs (range 33-74) and 33% of patients were self-reported Black. In cohort 1, 50% of patients were tx naive in this advanced setting, and 90% of patients had < 2 prior lines of tx. In cohort 2, 25% of patients had not received prior chemo in the metastatic setting. The overall ORR was 6%. One pt with TNBC had a complete response (CR). She received 36 cycles of tx; tx was discontinued due to mucositis and rash, and she remains in CR at >48 mos from start of tx. No patients in cohort 2 had a partial or complete response. The most common treatment-related adverse events were rash (61%), thyroid abnormality (17%), and pruritis (17%). 45% of patients experienced a grade 3 or 4 adverse event; all except one (hypokalemia) were due to rash. Rash was described as maculopapular dermatitis. The DCR at 18 weeks was 33.3% in the overall population; it was 44.4% in cohort 1 and 16.7% in cohort 2. Overall median PFS was 1.9 months 95% CI 1.8 – 3.6. Overall median OS was 12.9 months 95% CI 5.8 – 23.0. Conclusions: While this regimen demonstrated efficacy in a small subset of patients, including one pt with long-term CR, given the non-randomized design, we cannot determine if mifepristone enhanced the efficacy of ICI. In addition, a higher than anticipated rate of skin toxicity, possibly related to mifepristone enhancing the activity of ICI, was observed in the study, leading to early closure. While the benefit/risk analysis of this combination does not support further evaluation, additional investigation of alternative chemotherapy-free, immunomodulatory strategies is warranted. Clinical trial information: NCT03225547 .
Abstract
Background Estrogen receptor positive (ER+) progesterone receptor negative (PR-) tumors are a distinct subset of breast cancers that are not well characterized. It is critical to better ...understand the biology of ER+PR- tumors and tailor therapy accordingly for this unique subgroup. The objective of this study is to compare the ER+PR- subgroup of breast cancer as compared to the double positive ER+PR+ group in a large, well-characterized database to determine if the tumors that are PR- are associated with higher rates of genomic testing and chemotherapy receipt. Methods We identified patients diagnosed with ER+Her2-, Stage 1-3 invasive breast cancer from 2010-2015 in the National Cancer Database. We excluded patients who received neoadjuvant therapy. Demographics and clinical characteristics for the ER+PR+ and ER+PR- groups were obtained. Differences between groups were assessed using the chi-square test. Multivariable logistic regression analysis was performed on both the node negative and node positive patients in order to identify factors independently associated with having a genomic test and receiving chemotherapy in the ER+PR+ and ER+PR- cohorts. Results Of the 363,945 eligible patients, 327,357 (89.9%) patients had ER+PR+ breast cancer and 36,588 (10.1%) had ER+PR- breast cancer. A trend towards larger tumor size in the ER+PR- population as compared to the ER+PR+ population was noted with 23.1% vs 17.3% of tumors 2-5cm and 2.2% vs 1.2% of tumors > 5cm, respectively. Higher grade was also seen in the ER+PR- group as compared to the ER+PR+ group with 27.1% versus 11.7% grade 3 tumors. In both the node negative and node positive populations, genomic testing was less likely to be sent on a PR- breast cancer than a PR+ breast cancer. When genomic testing was sent, there were more high risk Oncotype Recurrence scores (RS > 30) in the PR- group than the PR+ group. For node negative breast cancer high risk Oncotype recurrence scores were found in 32.4% of the ER+PR- population versus 5.6% in the ER+PR+ population. In the node positive cohort high risk Oncotype Recurrence scores were seen in 27.8% of the ER+PR- population as compared to 5.0% in the ER+PR+ population. Patients with discordant ER+PR- breast cancer were more likely to receive chemotherapy than their ER+PR+ counterparts in both the node negative cohort (32.2% vs 12.7%) and the node positive cohort (73.2% vs 64.5%). Conclusion There have been limited studies to date specifically focused on the ER+PR- subgroup. Patients with ER+PR- breast cancer have a higher grade, larger size, higher risk genomic testing, and are more likely to receive chemotherapy than their ER+PR+ counterparts. Discordance in hormone receptor status contributes to a more aggressive type of breast cancer that may impact clinical and treatment decisions.
Citation Format: Poornima Saha, Angeline Yu, Priya Thakkar, Kristine Kuchta, Katharine Yao. Trends in clinical treatment of early stage ER+PR- breast cancer in the National Cancer Database abstract. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-02.
e13103
Background: Despite recent advances, treatment (tx) of metastatic triple-negative breast cancer (TNBC) remains an important unmet clinical need. Activation of the glucocorticoid receptor (GR) ...initiates cell survival pathways, leading to chemotherapy resistance. Furthermore, high GR expression is a negative prognostic marker in early-stage, hormone receptor negative breast cancer. We hypothesized that GR antagonism with mifepristone (mif) prior to the administration of cytotoxic chemotherapy would improve efficacy by blocking the potent anti-apoptotic signals mediated by GR activation. Methods: We conducted a phase II, randomized, placebo-controlled, multi-center study of nab-paclitaxel (nab-pac) with or without mif in patients (pts) with locally advanced, unresectable or metastatic TNBC (NCT02788981). Prior tx with nab-pac was not allowed. Two prior chemotherapies allowed in the metastatic setting. Pts were randomized to receive nab-pac 100mg/m
2
on day 1, 8, and 15 of a 28-day cycle with mif 300mg or placebo the day prior and day of each dose of nab-pac. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and safety and tolerability. Results: 29 patients were enrolled from September 2017 to July 2021; 16 patients were randomized to nab-pac+placebo and 13 patients to nab-pac+mif. The mean age was 53 years (range 32-73) and 34% of pts were self-reported Black. The median PFS was 3.0 and 3.0 months (mos) in the nab-pac alone and combination arms respectively (hazard ratio HR 0.87, 95% CI 0.37 – 2.01, p=0.739. ORR in the nab-pac and combination arms were 31.5% and 23%, respectively; both arms had 1 complete response (CR). Median OS with nab-pac alone was 6.0 mos and in the combination arm was 9.0 mos (HR=0.67, 95% CI 0.29 – 1.16, p=0.350. The pt on the mif arm who achieved a CR completed 50 cycles and ultimately died of a non-cancer, non-tx related event. Tx was generally well-tolerated, with a safety profile comparable with nab-pac monotherapy. The most common treatment-related adverse events (TRAEs) were fatigue (50%), neuropathy (42%), and neutropenia (42%); the most common grade 3 TRAE was neutropenia. Grade 3 neutropenia occurred more frequently in pts receiving nab-pac+mif (69% vs 13%). Conclusions: This study did not achieve the desired statistical power due to poor accrual attributed to the COVID-19 pandemic and the approval of checkpoint inhibitors in advanced TNBC. Nonetheless, in this subset of patients, the addition of mif to nab-pac did not significantly improve PFS compared to nab-pac alone. There was a trend towards improvement in OS, primarily driven by one long-term responder. GR activation remains relevant in advanced TNBC. Further investigation of this pathway and other strategies to target chemotherapy resistance are needed. Clinical trial information: NCT02788981 .
Abstract only
251
Background: A significant number of cancer-directed therapies are associated with cardiotoxicity. This adverse effect is well-established in anthracyclines and anti-HER2 agents. At ...our ambulatory oncology practice, the recent availability of echocardiograms with strain imaging has prompted an evaluation of current practices for cardiotoxicity monitoring. A review of the electronic health record (EHR) in 2019 found that although our institution maintains high rates of baseline monitoring, follow-up monitoring is not standardized and not consistent between different practices. Methods: A multidisciplinary team was formed to conduct a quality improvement project with the aim of increasing the rate of follow-up monitoring in patients who receive anthracyclines or infusional anti-HER2 agents. A survey of providers identified the potential reasons that follow-up cardiac monitoring was not completed. A Pareto chart showed that lack of familiarity with clinical necessity and appropriate timing were the most common barriers to follow-up monitoring. Our first plan-do-study-act focused on addressing these barriers, and a pilot in breast cancer treatment plans was started. Cardiac monitoring orders were added to curative intent protocols containing doxorubicin, trastuzumab, or pertuzumab. Education was provided to physician and nursing teams regarding utility and timing of cardiotoxicity monitoring. Collaboration with the cardiology group ensured timely access and result turnaround time. Results: An initial review of the EHR was conducted to identify current trends in cardiac monitoring. The review showed that there was an increase in the use of echocardiograms with strain imaging for baseline and follow-up monitoring in our patients. From January to April 2020, there was a total of 102 echocardiogram orders which was a 23% increase compared to the same timeframe in the previous year. The majority (61%) of those echocardiogram orders included strain imaging compared to 8% in the previous year. Review of treatment plan utilization and appropriate timing of cardiac monitoring in breast cancer patients is ongoing. Conclusions: This quality improvement project suggests that efforts to standardize cardiac monitoring practices can be achieved through provider education and workflow modifications. Further long-term review of the EHR will be needed to determine whether the timing of follow-up monitoring is appropriate and to identify what changes to the intervention should be made.
Abstract
Use of prognostic assays and clinical features to further risk stratify patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer ...has become standard of care. Stratification of patients into low/mid risk of disease recurrence enables physicians to decide which patients can safely forgo chemotherapy. Yet there exists a subpopulation of patients who tend to have recurrences following endocrine therapy alone. Complicating the issue, recent data has shown these proliferation-based markers assessed from a single site tissue biopsy may not be reliable for minority populations, potentially owing to spatial heterogeneity of tumors. To address this, we used a novel 2-paramenter pharmacokinetic modeling framework that allows biosignatures to be extracted from dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) studies that contain 3-6 timepoints spaced 60-90 seconds apart. These parameters, referred to as P1 and P2, represent leakiness from vessels into the extravascular space and vice versa. This approach was previously developed in a study of 111 breast cancer patients where the 21-gene recurrence score and DCE-MRIs were available. Low P1 showed better outcomes in low- and mid- patients (n=88, p≤0.028; log-rank test). Patients with a high P1 had a 20.2% chance recurrence at six years. The same trend was observed in mid-recurrence score patients only (n=23, p≤0.058). No recurrences were observed in patients with low P1 in either the RS-low or RS-mid categories. There were no recurrences in the high P1, RS-low/-mid category that received chemotherapy, suggesting that chemotherapy could be beneficial in this category of patients, although the trend was not statistically significant (n=10, p=0.46). Here we present an independent, single site validation of these prognostic markers in patients who received only neoadjuvant endocrine therapy and had corresponding pre-treatment MRIs. Two hundred ninety-eight patients with early-stage breast cancer and pre-treatment MRIs were identified via chart review. Of the patients assessed, 33 patients were treated with neoadjuvant endocrine therapy and qualified for the analysis. Consistent with the previous analysis, the 5-year event-free survival rate in low P1 population was 100% while that in the high P1 population was 45.8% (p=0.053). Overall, we find strong support that these markers could help physicians further fine tune their decision-making when determining who to forgo chemotherapy.
Citation Format: Joseph Peterson, Jose Rubio-Romera, Georgia Giakoumis Spear, Michele Britto, Bradley Hack, Tushar Pandey, Poornima Saha. Validation of prognostic platform to further refine identification High Risk Patients indicated for Chemotherapy Free Treatment in Early-Stage Breast Cancer abstract. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-36.
Abstract
Background: Minimal data exists for the utilization of the Oncotype Dx® assay specifically in breast cancers associated with BRCA1/2 pathogenic variants (PVs). It is unknown whether estrogen ...receptor positive (ER+) breast cancer associated with an inherited BRCA1 or BRCA2 (BRCA1/2) PV is more aggressive than disease seen in patients who do not carry an inherited PV, and whether there are differences between BRCA1 and BRCA2. In prostate cancer patients with inherited cancer predisposition due to a BRCA2 PV, more aggressive cancers are observed, which influences first-line treatment. Limited data exists for the optimal management of early stage ER+ breast cancer in BRCA1/2 PV carriers. Comparing Recurrence Score® (RS) results in ER+ breast cancer patients with an inherited BRCA1/2 PV (cases) versus matched patients who test negative for a PV in BRCA1/2 (controls) may inform whether biologically more aggressive breast cancer is seen in BRCA1/2 carriers and optimal treatment approaches. Methods: A retrospective case control study was performed to compare RS results in women with breast cancer with an inherited BRCA1/2 PV versus patients who tested negative for an inherited BRCA1/2 PV. Female breast cancer patients seen between 2005-2020 at NorthShore University Health System with ER+Her2- early stage invasive breast cancer with 0-3 lymph nodes who completed genetic testing for BRCA1/2 were eligible for enrollment. BRCA1/2 cases were defined as individuals with an inherited PV in BRCA1/2 and controls were negative for BRCA1/2 or other known breast cancer risk gene PVs tested. Subjects were excluded if they had neoadjuvant therapy (hormonal or cytotoxic chemotherapy). Eligible cases were matched to control patients by age, grade, and stage. The Recurrence Score result was obtained by chart review; if not previously evaluated, Oncotype Dx assay was performed by Exact Sciences. Statistical analysis of the primary outcome used the paired t-test to determine mean difference in RS results between BRCA1/2 PV carriers and patients negative for a PV in BRCA1/2 using a 1:1 matched pairs design. Results: A total of 46 matched cases and controls were analyzed. Median age was 50 with a range of 28-74. Of the cases, 18 had a BRCA1 PV and 28 had a BRCA2 PV. Cases and controls were well matched for age (> 50 and ≤ 50); race, grade, stage, and progesterone receptor status. As expected, a higher number of BRCA1/2 carriers were treated with mastectomy while more of the controls received breast-conserving surgery. Chemotherapy was utilized more frequently in the cases (67.4%) versus the controls (54.4%). The average RS result was higher in the cases (27) than the controls (21.3) by a mean difference of 5.7 (p = 0.0195). Using Oncotype Dx cutoffs of low < 18, intermediate 18-30 and high ≥ 31, a statistically significant difference in RS result was noted in the cases versus controls. For cases in the highest risk group (Oncotype Dx ≥ 31), only 20% of their matches also had a score in the highest risk group while 35% had a score in the lowest risk group. Subgroup analysis showed that the cases had the largest difference in RS result from their controls in premenopausal women (age ≤ 50), BRCA1 carriers, and the node negative population. Conclusion We present one of the largest data sets available to date of a well-matched cohort of cases and controls which shows that BRCA1/2 PV carriers are more likely to have a higher Recurrence Score result than their matched controls when matched for age, grade, and stage. These findings suggest ER+ breast cancer in BRCA1/2 PV carriers is biologically more aggressive. Further investigation is warranted to evaluate how this important finding impacts adjuvant therapy recommendations for BRCA1/2 PV carriers.
Citation Format: Poornima Saha, Ashley Aller, Amanda Deliere, Peter Hulick, Katharine Yao, Kristine Kuchta, Megan Sullivan, Allison DePersia. Application of 21-gene Breast Recurrence Score® assay to evaluate prognosis and benefit of adjuvant chemotherapy in BRCA1 and BRCA2 pathogenic variant carriers with early stage, estrogen receptor positive breast cancer abstract. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-15.
PDF
