Correlating Predicted Adjuvant Therapy Benefit and Risk of Recurrence Between Breast Cancer Index (BCI) and the 21-Gene Oncotype DX Recurrence Score (RS).

INTRODUCTION: Breast Cancer Index (BCI) is a genomic assay that evaluates the benefit of extending endocrine therapy (ET) from 5 to 10 years and predicts recurrence risk (RR). We evaluated the association between BCI and Oncotype DX (ODX). PATIENTS: Women with hormone receptor (HR)-positive early-stage breast cancer (EBC) who had BCI and ODX performed were included. METHODS: We performed a retrospective review of women with HR-positive EBC. BCI was categorized as predictive of extended ET versus not and ODX recurrence score (RS) as low (0-10), intermediate (11-25), and high (26-100). Univariate and multivariable logistic and linear regression models assessed the relationship between BCI and ODX, factors associated with each, and discordance between scores. RESULTS: We identified 153 women, 22% were premenopausal and 18% were lymph node positive. The univariate logistic and linear models revealed an association between BCI predictive score and ODX RS (OR 7.84, CI, 2.63-23.36, P < .001) and log of BCI RR (Beta 0.04, CI, 0.02-0.06, P < .001). Seventy-four percent of BCI predictive scores were concordant with ODX RS and 83% of BCI RR was concordant with ODX RR. In a univariate logistic regression model, BCI predictive of ET benefit was associated with discordance (OR 28.00, CI, 10.58-74.02, P < .001). Higher ODX RR was associated with discordance (OR 1.92, CI, 1.42-2.59, P < .001). CONCLUSION: We found a significant association between ODX and BCI predictive and prognostic scores. BCI predictive of extended ET benefit was associated with discordance with ODX RS. Higher predicted RR on ODX was associated with discordance with BCI predicted RR.

Results of a Phase Ib Study Investigating Durvalumab in Combination with Eribulin in Patients with HER2-Negative Metastatic Breast Cancer and Recurrent Ovarian Cancer.

INTRODUCTION: The release of tumor-associated antigens with cytotoxic chemotherapy treatment may enhance the response to immune checkpoint blockade. Eribulin is a microtubule inhibitor with proven overall survival (OS) benefit in metastatic breast cancer (MBC), which may also enhance intratumoral vascular remodeling. Durvalumab, a humanized monoclonal antibody, targets the programmed cell death ligand-1 (PD-L1) receptor. This study sought to determine the maximum tolerated dose and recommended phase II dose (RP2D) of eribulin in combination with durvalumab, as well as the safety and preliminary antitumor activity of the combination in patients with previously treated HER2-negative (HER2-) MBC and recurrent ovarian cancer (ROC). METHODS: Cohorts of 3-6 patients with HER2- MBC and ROC were treated in a modified 3+3 design. Eligible patients received escalating doses of eribulin (1.1 mg/m2 or 1.4 mg/m2 IV on day 1 and day 8) with durvalumab (1.12 g IV on day 1) in 21-day cycles until dose-limiting toxicity (DLT), intolerable adverse events (AEs), disease progression, or other reasons for withdrawal. PRIMARY ENDPOINT: the rate of DLTs during cycles 1 and 2 of therapy. Secondary endpoints: AE rate, objective response rate (ORR), progression-free survival (PFS), and OS. RESULTS: Nine patients with a median of 4 prior therapies for advanced disease were treated: 5 patients with HER2- MBC (1 with triple-negative disease and 4 with hormone-positive disease) and 4 patients with ROC. The RP2D of eribulin was 1.4 mg/m2 in combination with durvalumab. There were no DLTs experienced during the first two cycles of therapy. The most common treatment-related AEs (>50%) were fatigue, neutropenia, decreased white blood cell count, anemia, AST and alkaline phosphatase elevation, hyperglycemia, and nausea; most were grade 1 or 2. There was one immune-related AE of grade 3 (hepatitis) after 5 cycles of treatment, for which patient came off study. Two other patients discontinued study drug related to toxicity (neutropenia [n = 1], hepatic toxicity [n = 1]). ORR was 55%, and 4 additional patients experienced stable disease. All MBC patients exhibited a response to therapy. Median PFS was 6.2 months. Median OS was 15.0 months. CONCLUSION: The combination of eribulin at a dose of 1.4 mg/m2 with standard dose durvalumab had a favorable AE profile in patients with previously treated HER2- MBC and ROC. The early antitumor activity observed in all MBC patients enrolled in the study suggests that further investigation of this combination is warranted.

Secondary Invasive Breast Events among Patients with Hormone-Positive Breast Cancer and High-Risk Oncotype DX Recurrence Scores 26-30 and ≥31.

BACKGROUND: The Oncotype DX Recurrence Score (ODx RS) is the most widely adopted genomic assay used to guide treatment for patients with early-stage, hormone-positive (HR+) breast cancer (BC), with higher scores predicting greater risk of recurrence and benefit from chemotherapy. Patients with ODx RS >25 typically recieve adjuvant chemotherapy; however, data regarding efficacy of chemotherapy for reducing recurrence in this population have been mixed. OBJECTIVES: This study aimed to evaluate outcomes of patients with early-stage HR+ BC with high-risk ODx RS (26-30 and ≥31) in order to assess treatment patterns and outcomes. We hypothesized that the benefit of chemotherapy in these groups may be minimal and that select patients may forgo chemotherapy in favor of more aggressive endocrine therapy and ovarian suppression. METHODS: We performed a retrospective analysis of 515 patients with early-stage, HR+ BC with high-risk ODx RS 26-30 and ≥31 treated between 2006 and 2018. Patients were stratified by RS: low-risk (≤10), intermediate-risk (11-25), and high-risk (≥26). The Kaplan-Meier method was used to estimate the time to secondary invasive breast events (SIBE) or distributions overall and among different RS groups with the log rank test used to compare distributions between groups. RESULTS: Rates of chemotherapy administration were 7% among the low-risk group, 18% among the intermediate-risk group, and 83% among high-risk patients with 41 SIBE (8%) reported. When stratified by ODx RS, 5-year rates of SIBE were 4%, 6%, and 16% for low-risk, intermediate-risk, and high-risk RS, respectively. Among the 27 lymph node (LN)-negative patients with ODx RS 26-30, 74% received chemotherapy. The 5-year rate of SIBE was 25% among patients who received chemotherapy and 33% among those who did not (p = 0.5489). Among the 23 LN-negative patients with ODx RS ≥31, 91% of patients received chemotherapy. The 5-year rate of SIBE was 0% both with and without chemotherapy. CONCLUSIONS: There was no statistically significant difference in SIBE for patients with high-risk ODx RS based on chemotherapy treatment. More aggressive endocrine therapy with ovarian suppression has become an alternative to chemotherapy among patients with intermediate-risk ODx RS (16-25). This approach may be useful among patients with high-risk ODx RS, with additional studies needed in this patient population.

Diabetes and Metformin Association with Recurrence Score in a Large Oncotype Database of Breast Cancer Patients.

BACKGROUND: The Oncotype DX® (ODX) is a genomic assay that provides clinicians with a prediction of benefit of chemotherapy in node-negative, tamoxifen-treated breast cancer. However, the relationship between ODX recurrence score (RS) and diabetes, a common comorbidity in breast cancer patients, has been inadequately described in the literature. Specifically, the association of diabetes treatment with metformin and RS is inconclusive, with different studies reporting conflicting results. Because diabetes has been associated with higher RS, it has been suggested that management of diabetes with metformin in breast cancer patients may be associated with a lower RS. OBJECTIVES: We studied a large cohort of early-stage, hormone-positive breast cancer patients to determine if there is an association between RS and metformin treatment. METHODS: In this study, we retrospectively examined the medical records of 514 early-stage, hormone-positive breast cancer patients who had oncotype testing performed between 2007 and 2017. Number (%) or median were used to describe the patients' characteristics between groups and were compared by the Kruskal-Wallis test at a significance level of 5%. RESULTS: Of this cohort, 67 (13%) had a diabetes diagnosis at the time of breast cancer diagnosis, including both diabetes mellitus and pre-diabetes. The median RS for non-diabetic patients was 16 and the median RS for diabetic patients was 15. This difference was not significant, nor was there a statistical difference in RS between diabetic patients taking metformin (median RS = 15) and diabetic patients not taking metformin (median RS = 15). These results held true even when controlling for BMI. CONCLUSIONS: We conclude that neither diabetes diagnosis nor metformin use is associated with a difference in oncotype RS in this population of diabetic patients.

BRCA Mutation Association with Recurrence Score and Discordance in a Large Oncotype Database.

BACKGROUND: The Oncotype DX Breast Cancer Assay is a 21-gene assay used to predict the likelihood of distant recurrence and the benefit of chemotherapy in patients with node-negative, tamoxifen-treated breast cancer. Prior studies demonstrated 7-19% discordance, or a difference between the recurrence score (RS) and tumor grade (TG) in breast cancer patients. BRCA mutated tumors (BRCA+) have been shown to be associated with higher RS as compared to BRCA-negative patients (BRCA-). OBJECTIVES: We developed a large Oncotype RS database to determine if the BRCA mutation status is associated with discordance. METHODS: We identified 723 patients (32 [4%] mutation-positive and 691 [96%] mutation-negative patients) with early-stage, hormone-positive breast cancer treated between 2006 and 2018, with tumor characteristics available for analysis. Discordance was defined as one- or two-step difference between RS (low, intermediate, high risk) and TG (well [WD], moderately [MD], and poorly [PD] differentiated). Mutation positive was defined as BRCA1 deleterious mutation, BRCA2 deleterious mutation, BRCA mutation of unknown type, BRCA variant of undetermined significance (VUS) or other mutation (classified as other VUS). Number (%) or median were used to describe patient characteristics between groups and were compared by the Kruskal-Wallis test at a significance level of 5%. RESULTS: Among these patients, there were 32 (4% of total) who were identified as mutation-positive. Of those patients, 16% had a documented deleterious mutation in BRCA1, 22% in BRCA2, 6% had a BRCA mutation of unknown type (either 1 or 2), 25% were BRCA VUS, and 31% other VUS (most commonly CHEK2 and ATM). The median RS was 23.5 in patients with deleterious BRCA mutations (1, 2 or unknown) versus 16 in patients in the BRCA-negative database, which was statistically significant (p < 0.01). One- and two-step discordance was present in 46 and 8%, respectively, of patients with deleterious BRCA mutations versus 53 and 11%, respectively, in the BRCA-negative database. CONCLUSIONS: Patients with deleterious BRCA mutations demonstrated no difference in rates of discordance as compared to BRCA-negative patients. We further demonstrated that patients with BRCA-positive tumors display higher RS than patients with BRCA-negative tumors.

The Preventive Role of Angiotensin Converting Enzyme Inhibitors/Angiotensin-II Receptor Blockers and ß-Adrenergic Blockers in Anthracycline- and Trastuzumab-Induced Cardiotoxicity.

Anthracycline (doxorubicin) and trastuzumab treatments for cancer patients have been known to cause cardiotoxicity. The current recommendations for prevention of cardiac events from cancer chemotherapies are largely based on opinion. The American Society of Clinical Oncology recommends active screening and prevention of modifiable cardiovascular risk factors. The risk factors are defined as tobacco use, high blood pressure, high cholesterol, alcohol use, obesity, and physical inactivity. Beta-adrenergic blockers and angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) have been the mainstay of treatment for heart failure patients with reduced left ventricular ejection fraction for many years. This review analyzed the use of beta-adrenergic blockers and ACE inhibitors/ARBs as protection against cardiomyopathy caused by anthracyclines and trastuzumab. Although many more studies are warranted, it was concluded that the addition of a beta-blocker early in the treatment of cancer patients who are undergoing anthracycline or trastuzumab treatment can have beneficial effects in preserving left ventricular ejection fraction and preventing chemotherapy-induced cardiotoxicity. The effects are more apparent in the short term. More studies of the long-term effects are warranted, as are the additive effects of using a beta-blocker and ACE inhibitor/ARB together to prevent chemotherapy-induced cardiotoxicity.