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Purpose: One year of neratinib therapy is known to derive a significant invasive disease-free survival (iDFS) benefit in early-stage, hormone receptor-positive (HR +), HER2 + , node-positive breast cancer after trastuzumab-based adjuvant therapy. Limitations to neratinib use include significant gastrointestinal side effects, which often result in treatment discontinuation. In this study, we aimed to identify clinicopathologic features associated with adjuvant neratinib use and factors impacting treatment completion. Methods: We performed a retrospective review of patients with early-stage HR + HER2 + breast cancer who were prescribed neratinib from 2017 to 2023 at our institution. We used the electronic medical record to extract information on patient characteristics, clinical features, and treatment information. Patients were identified as high risk based on definitions adapted from the standard high-risk definition in HR + HER2- breast cancer combined with studies correlating high Ki67 or high tumor grade with lower recurrence-free survival. Statistical analysis was performed using two-sided T-tests and chi-square tests. Results: We identified 62 eligible patients of whom 55% completed 1 year of neratinib and 45% did not. Sixty percent (N = 37) of patients offered neratinib were considered high risk at diagnosis. The most common reason for neratinib discontinuation was inability to tolerate side effects (54%) followed by pill burden (18%). The most common side effect experienced by patients was diarrhea despite anti-diarrheal prophylaxis (56%), followed by rash (8%). Patients who received an up-titration of neratinib were more likely to complete the full course of neratinib when compared to those who did not (76% vs. 40.5% p = 0.013). The median starting dose of those who completed neratinib treatment was 140 vs. 240 mg in those who did not (p = 0.016). Neither group experienced a statistically significant greater likelihood of treatment holds or dose reductions. In terms of outcomes, 10 patients had progression of disease of whom 7 did not complete neratinib treatment (p = 0.169). Interestingly, those 7 patients developed metastatic disease and 57% (N = 4) had central nervous system metastases. Conclusion: Patients are more likely to complete 1 year of adjuvant neratinib with dose up-titration. Dose reductions and interruptions did not affect neratinib adherence in our patient population. Seven patients (11%) in our study developed metastatic disease, all of whom did not complete adjuvant neratinib treatment. [ABSTRACT FROM AUTHOR]

Purpose: We hypothesized that eribulin combined with cyclophosphamide (EC) would be an effective combination with tolerable toxicity for the treatment of advanced breast cancer (ABC). Methods: Patients with histologically confirmed metastatic or unresectable ABC with any number of prior lines of therapy were eligible to enroll. In the dose escalation cohort, dose level 0 was defined as eribulin 1.1 mg/m2 and cyclophosphamide 600 mg/m2, and dose level 1 was defined as eribulin 1.4 mg/m2 and cyclophosphamide 600 mg/m2. Eribulin was given on days 1 and 8 and cyclophosphamide on day 1 of a 21-day cycle. In the dose expansion cohort, enrollment was expanded at dose level 1. The primary objective was clinical benefit rate (CBR), and secondary objectives were response rate (RR), duration of response (DOR), progression-free survival (PFS), and safety. Results: No dose-limiting toxicities were identified in the dose escalation cohort (n = 6). In the dose expansion cohort, an additional 38 patients were enrolled for a total of 44 patients, including 31 patients (70.4%) with hormone receptor-positive (HR +)/HER2- disease, 12 patients (27.3%) with triple-negative breast cancer (TNBC), and 1 patient (2.3%) with HR + /HER2 + disease. Patients had a median age of 56 years (range 33–82 years), 1 prior line of hormone therapy (range 0–6), and 2 prior lines of chemotherapy (range 0–7). CBR was 79.5% (35/44; 7 partial response, 28 stable disease) and the median DOR was 16.4 weeks (range 13.8–21.1 weeks). Median PFS was 16.4 weeks (95% CI: 13.8–21.1 weeks). The most common grade 3/4 adverse event was neutropenia (47.7%, n = 21). Fourteen of 26 patients (53.8%) with circulating tumor cell (CTC) data were CTC-positive (≥ 5 CTC/7.5 mL) at baseline. Median PFS was shorter in patients who were CTC-positive vs. negative (13.1 vs 30.6 weeks, p = 0.011). Conclusion: In heavily pretreated patients with ABC, treatment with EC resulted in an encouraging CBR of 79.5% and PFS of 16.4 weeks, which compares favorably to single-agent eribulin. Dose reduction and delays were primarily due to neutropenia. The contribution of cyclophosphamide to eribulin remains unclear but warrants further evaluation. NCT01554371. [ABSTRACT FROM AUTHOR]

Purpose: The incidence of breast cancer in young women (BCYW) has increased in recent decades. Malignant disease in this subset is characterized by its aggressiveness and poor prognosis. Ovarian function suppression (OFS) in these patients improves survival especially in hormone receptor-positive (HR +) cases. The Regan Composite Risk (RCR) is a prognostic tool to identify high-risk HR + BC candidates for OFS. Our study sought to characterize a Chilean cohort of early HR + BCYW assessing the use of OFS and its related prognosis and the utility of RCR in our patients. Methods: This was a retrospective population cohort study that included ≤ 35-year-old early HR + /human epidermal growth factor receptor 2 -negative (HER2-) BC patients treated between 2001 and 2021. Analysis included clinical-pathological characteristics, treatment strategies, and survival. Also, we evaluated the association between RCR and survival. Results: A total of 143 patients were included into our study, representing 2.9% of all early BC cases in our registry. Median age was 31 years old (range: 19–35). Most patients (93%) received endocrine therapy (ET). Of these, 18% received OFS. No survival differences were observed among treatment strategies. Median RCR score for patients treated with CT plus ET was significantly higher vs. ET alone (2.95 vs. 1.91; p = 0.0001). Conversely, patients treated with tamoxifen alone had significantly lower RCR scores vs. OFS (2.72 vs. 3.14; p = 0.04). Higher RCR scores were associated with poorer overall survival. Conclusion: Less than 20% of very young women with early HR + /HER2-BC in our cohort received OFS, in most cases, this involved surgical oophorectomy. RCR score was higher in patients that underwent CT and OFS and was associated with survival, regardless of treatment. We confirm the RCR score as a valuable prognostic tool to identify high-risk BC patients who could benefit from OFS. [ABSTRACT FROM AUTHOR]

Purpose: Optimal extended adjuvant endocrine therapy (ET) duration and strategy for hormone receptor-positive (HR +) early breast cancer remain unclear. In this network meta-analysis (NMA), the efficacy and safety of all available extended adjuvant ETs were compared and ranked. Methods: PubMed, Embase, and Cochrane Library and abstracts presented at ASCO, SABCS, and ESMO were searched on March 5, 2022. Fourteen randomized controlled trials (RCTs) comprising eight extended adjuvant ETs for HR + breast cancer and 38,070 patients were analyzed. Main outcomes were disease-free survival (DFS), overall survival (OS), grade ≥ 3 adverse events (AEs), and contralateral breast cancer (CBC). Direct and indirect comparisons were integrated via Bayesian NMA. Hierarchical cluster analysis was performed to jointly rank efficacy and safety outcomes. Results: Compared with that of 5 year ET, extended 10 year aromatase inhibitor (AI) treatment provided the greatest DFS benefit (HR = 0.45, 95%CrI 0.23–0.83), whereas no strategy differed significantly in terms of the other main outcomes. Extended 10 year AI treatment was the preferred strategy for DFS improvement and CBC prevention (surface under the cumulative ranking curve: 93.51% and 91.29% probability, respectively). All strategies had comparable safeties (grade ≥ 3 AEs). Compared with that of 5 year ET, 10 year extended AI significantly increased arthralgia (OR = 1.65, 95%CrI 1.02–2.93) and osteoporosis (OR = 3.33, 95%CrI 1.19–9.68). Conclusion: Extended 10 year AI therapy may be optimal for HR + early breast cancer given its relatively high efficacy and safety. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the effectiveness of ovarian function suppression (OFS) of various gonadotropin-releasing hormone agonists (GnRHa) combined with aromatase inhibitors (AI) in premenopausal patients with hormone receptor-positive (HR-positive) breast cancer. Potential risk factors associated with insufficient OFS were analyzed. Patients and methods: Premenopausal HR-positive breast cancer patients who had received AI with GnRHa were studied retrospectively. Patients were divided into different groups according to monthly or trimonthly GnRHa schedules they received, and the effectiveness of OFS was compared between groups. Insufficient OFS was defined as at least one instance of estradiol ≥ 30 pg/ml. Patient data was gathered from medical records for this comparison. Results: Of the 264 patients enrolled in this study, 117 were administered 3.6 mg of goserelin monthly (goserelin 1 M group), 63 received 3.75 mg of leuprorelin monthly (leuprorelin 1 M group) and 84 were given 11.25 mg of leuprorelin every three months (leuprorelin 3 M group). Overall, 7.20% experienced insufficient OFS. The incidence rates in the three GnRHa depot groups were 7.69%, 6.35%, and 7.14%, respectively, without a significant statistical difference (P = 0.900). Notably, younger patients exhibited a higher likelihood of insufficient OFS [OR = 0.900, 95%CI (0.824–0.982), P = 0.018]. Conclusion: Insufficient OFS remains a concern during GnRHa and AI treatment. The effectiveness of the three GnRHa depots commonly used in China seems comparable. Younger patients face a heightened risk of insufficient OFS. [ABSTRACT FROM AUTHOR]

Purpose: The role of neoadjuvant endocrine therapy in the treatment of patients with early-stage, hormone receptor-positive (HR +) breast cancer is not well defined. Tools to better determine which patients may benefit from neoadjuvant endocrine therapy versus chemotherapy or upfront surgery remain an unmet need. Methods: We assessed the rate of clinical and pathologic complete response (cCR, pCR) among a pooled cohort of patients with early-stage HR + breast cancer who had been randomized to neoadjuvant endocrine therapy or neoadjuvant chemotherapy in two earlier studies to understand better how outcomes varied by Oncotype DX Breast Recurrence Score® assay. Results: We observed that patients with intermediate RS results had no statistically significant differences in pathologic outcomes at the time of surgery based on whether they received neoadjuvant endocrine therapy or neoadjuvant chemotherapy, suggesting that a subgroup of women with a RS 0–25 may omit chemotherapy without compromising outcomes. Conclusion: These data suggest that Recurrence Score® (RS) results may serve as a useful tool in treatment decision-making in the neoadjuvant setting. [ABSTRACT FROM AUTHOR]

Purpose: Dual anti-HER2 targeted therapy and chemotherapy is the current first-line standard of care for HER2 + metastatic breast cancer (MBC), with endocrine therapy (ET) the backbone of treatment in hormone receptor positive (HR +) disease. The potential ET benefit in HER2 + /HR + patients is unknown as pivotal dual anti-HER2 clinical trials precluded ET use. Methods: Real-world data from a multi-site registry of consecutive HER2 + MBC patients treated at clinician discretion were examined. Patients that were HR + (ER + and/or PR +) and had received first-line chemotherapy alongside trastuzumab and pertuzumab were explored. Of 362 patients in the registry, 215 were excluded due to being HR- (n = 210) or not receiving chemotherapy (n = 5). Results: Of the 147 patients included, 91 (62%) received concurrent ET and 56 (38%) had not. Comparing the groups, there were no significant differences in age, performance status, metastatic sites, use of previous therapy and de novo metastatic disease. More patients with ER + PR + disease versus those with ER + PR- or ER-PR + received ET (73 vs 45%). The addition of ET was associated with significantly improved 5-year PFS (HR 0.58, CI 0.37–0.89, p = 0.014) and OS (HR 0.52, CI 0.31–0.90, p = 0.018), with no increase in adverse events noted. Conclusion: The addition of ET to first-line dual anti-HER2 therapy post chemotherapy in patients with HER2 + /HR + MBC was associated with major gains in PFS and OS with no safety concerns evident. Further studies of this combination are justified, along with studies of how best to integrate other agents that are active in this patient subset, including CDK4/6 inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: Dual anti-HER2 targeted therapy and chemotherapy is the current first-line standard of care for HER2 + metastatic breast cancer (MBC), with endocrine therapy (ET) the backbone of treatment in hormone receptor positive (HR +) disease. The potential ET benefit in HER2 + /HR + patients is unknown as pivotal dual anti-HER2 clinical trials precluded ET use. Methods: Real-world data from a multi-site registry of consecutive HER2 + MBC patients treated at clinician discretion were examined. Patients that were HR + (ER + and/or PR +) and had received first-line chemotherapy alongside trastuzumab and pertuzumab were explored. Of 362 patients in the registry, 215 were excluded due to being HR- (n = 210) or not receiving chemotherapy (n = 5). Results: Of the 147 patients included, 91 (62%) received concurrent ET and 56 (38%) had not. Comparing the groups, there were no significant differences in age, performance status, metastatic sites, use of previous therapy and de novo metastatic disease. More patients with ER + PR + disease versus those with ER + PR- or ER-PR + received ET (73 vs 45%). The addition of ET was associated with significantly improved 5-year PFS (HR 0.58, CI 0.37–0.89, p = 0.014) and OS (HR 0.52, CI 0.31–0.90, p = 0.018), with no increase in adverse events noted. Conclusion: The addition of ET to first-line dual anti-HER2 therapy post chemotherapy in patients with HER2 + /HR + MBC was associated with major gains in PFS and OS with no safety concerns evident. Further studies of this combination are justified, along with studies of how best to integrate other agents that are active in this patient subset, including CDK4/6 inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: Resistance to endocrine therapy poses a major clinical challenge for patients with hormone receptor-positive (HR +), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC). We present the preplanned 24-month final overall survival (OS) results, alongside updated progression-free survival (PFS), and objective response rate (ORR) results. Methods: nextMONARCH is an open-label, controlled, randomized, Phase 2 study of abemaciclib alone or in combination with tamoxifen in women with endocrine-refractory HR + , HER2– MBC previously treated with chemotherapy. Patients were randomized 1:1:1 to: abemaciclib 150 mg and tamoxifen 20 mg (A + T), abemaciclib 150 mg (A-150), or abemaciclib 200 mg and prophylactic loperamide (A-200). OS was the main prespecified secondary endpoint. PFS, ORR, and safety at 24 months were compared to previously reported primary analysis results. Results: Of the 234 patients enrolled, 12 were receiving study treatment at data cutoff (28Jun2019). Median follow-up was 27.2 months. Median OS was 24.2 months in the A + T arm, 20.8 months in A-150, and 17.0 months in A-200 (A + T versus A-200: HR 0.62; 95%CI [0.40, 0.97], P = 0.03 and A-150 versus A-200: HR 0.96; 95%CI [0.64, 1.44], P = 0.83). PFS and ORR results at 24 months were consistent with the primary analysis. The safety profile corresponded with previous reports. Conclusion: The addition of tamoxifen to abemaciclib demonstrated greater OS benefit than monotherapy. This study confirmed the single-agent activity of abemaciclib in heavily pretreated women with endocrine-refractory HR + , HER2– MBC, as well as the previously reported primary PFS and ORR results, with no new safety signals observed. Trial Registration ClinicalTrials.gov Identifier: NCT02747004. [ABSTRACT FROM AUTHOR]

Purpose: Neoadjuvant endocrine therapy (NET) facilitates clinical response and breast conservation in hormone receptor-positive (HR-positive) breast cancer. Patient selection for adjuvant chemotherapy (CT) post-NET is unclear and potentially evolving with use of genomic assays. We evaluated post-NET CT use in a national dataset. Methods: Using the National Cancer DataBase, we identified patients with cT2-3N0-3M0 HR-positive/human epidermal growth factor receptor 2-negative breast cancer treated between 2010 and 2017 with 3–12 months of NET prior to breast surgery. CT use was evaluated in the overall population, in patients with a pathologic complete response (pCR) and in patients with ypT1-2N0 disease (approximating PEPI 0). Exploratory analysis included patients > 50 years with ypN0-1, and 21-gene recurrence score (RS) ≤ 25 (approximating TAILORx/RxPONDER populations not benefiting from CT). Multivariable logistic regression was used to identify factors associated with CT. Results: Among 3624 eligible patients, 20.4% (740/3624) received CT. On multivariable analysis, age ≤ 50, lobular histology, grade 2, progesterone receptor negativity, ypT3, ypN + and RS ≥ 18 were associated with CT receipt. Co-morbidity, longer NET duration, ypT4, ypNx, and RS < 18 were associated with CT omission. CT was administered to 3.3% (1/30) of patients experiencing pCR and 5.5% (82/1483) with ypT1-2N0 disease. Among patients > 50 years with ypT0-3N0-1 residual disease, 13.8% (355/2569) received CT; RS was available for 24.8% (88/355) and 60% (53/88) had a score 0–25. Conclusion: A minority of patients receive CT post-NET. This decision appears to be driven by younger age, RS and pathological nodal status. Increased consideration of these factors prior to neoadjuvant treatment choice may be warranted. [ABSTRACT FROM AUTHOR]

Purpose: CompLEEment-1 is a phase 3b trial in an expanded patient population with hormone receptor-positive (HR +), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC), the largest current trial of cyclin-dependent kinase 4 and 6 inhibitors in ABC. Methods: Patients treated with ≤ 1 line of prior chemotherapy and no prior endocrine therapy for ABC received ribociclib 600 mg/day (3-weeks-on/1-week-off) plus letrozole 2.5 mg/day and additionally monthly goserelin/leuprolide in men and pre-/perimenopausal women. Eligibility criteria allowed inclusion of patients with stable CNS metastases and an Eastern Cooperative Oncology Group performance status of 2. Primary objectives were safety and tolerability, and secondary objectives were efficacy and quality of life (QoL). Results: Overall, 3,246 patients were evaluated (median follow-up 25.4 months). Rates of all-grade and grade ≥ 3 treatment-related adverse events (AEs) were 95.2% and 67.5%, respectively. Treatment-related discontinuations due to all grade and grade ≥ 3 AEs occurred in 12.9% and 7.3% of patients, respectively. Rates of all-grade AEs of special interest (AESI) were as follows: neutropenia (74.5%), increased alanine aminotransferase (16.2%), increased aspartate aminotransferase (14.1%), and QTcF prolongation (6.7%); corresponding values for grade ≥ 3 AESI were 57.2%, 7.7%, 5.7%, and 1.0%, respectively. Median time to progression was 27.1 months (95% confidence interval, 25.7 to not reached). Patient QoL was maintained during treatment. Conclusion: Safety and efficacy data in this expanded population were consistent with the MONALEESA-2 and MONALEESA-7 trials and support the use of ribociclib plus letrozole in the first-line setting for patients with HR + , HER2– ABC. Trial registration: linicalTrials.gov NCT02941926. [ABSTRACT FROM AUTHOR]

Purpose: To investigate predictors of treatment interruption and early discontinuation of adjuvant hormonal therapy (HT) in a retrospective cohort of women with newly diagnosed hormone receptor-positive (HR +) breast cancer. Methods: Eligible cases were identified from a single institutional tumor registry from 2009 to 2015. Patients were followed from initiation of adjuvant HT for a minimum of one year through December 1, 2016. Predictors of treatment interruption or early discontinuation were analyzed with Cox proportional hazards regression models. Results: With a median follow-up time of 3.0 years (IQR 1.5–4.5), 22 women (10.9%) discontinued HT early and 47 (23.4%) had at least one treatment interruption of > 14 days. Adjusted Cox proportional hazards regression models showed that women with pre-existing affective disorders were more likely to discontinue therapy early (HR 3.15; 95% CI 1.35–7.37), while those with pre-existing chronic pain disorders were at increased risk for treatment interruption (HR 2.24; 95% CI 1.20–4.19). HT-related symptoms were the most commonly reported reason for HT interruption or discontinuation. Women who experienced severe treatment-related symptoms were at increased risk for both HT interruption (HR 2.64; 95% CI 1.07–6.50) and HT discontinuation (HR 3.48; 95% CI 1.20–10.1). Conclusions: This study showed that HT interruptions and discontinuation were common, often associated with HT-related symptoms. Clinicians caring for breast cancer patients on HT should monitor closely for treatment-emergent symptoms, especially women with pre-existing disorders, and support them to continue therapy through aggressive symptom management and other patient-centered approaches. [ABSTRACT FROM AUTHOR]

Background: Over the last 20 years, aromatase inhibitors (AI) have been tested in clinical trials as first-line therapy for hormone receptor-positive (HR-positive) advanced breast cancer (ABC), firstly as experimental arms, when they proved to be effective, and recently as control arms. This analysis aims to evaluate trends in progression-free survival (PFS) and time to progression (TTP) over time.Patients and methods: A literature review was conducted using the MEDLINE database to identify randomized controlled phase II or III trials which reported PFS or TTP of at least one arm using first-line AI HR-positive ABC patients. A linear correlation was used to access the association between the year of the first patient enrolled and the observed PFS/TTP.Results: The search retrieved 19 trials, accounting for 4552 postmenopausal patients divided into 21 separate AI treatment arms. The PFS/TTP increased from 6 to 9 months in the earlier trials to 13-16 months in the current era, representing an absolute gain of approximately 7 months, without the addition of any other drug. Our analysis showed a positive correlation between the year of the first patient enrolled in these trials and median PFS/TTP reported (R2 = 0.34; p < 0.01). No correlation was found between the year of the first patient included in these trials and other potential prognostic factors such as visceral metastasis at baseline (R2 = 0.26; p = 0.20) or exposure to adjuvant therapy (R2 = 0.05; p = 0.18).Conclusion: Patients treated with first-line AIs in the more recently conducted trials have longer PFS/TTP when compared to their counterparts treated with the same drugs in older studies. These findings have important implications for the estimation of sample size and follow-up periods for the planning of future trials as well as in the translation of the results into clinical practice decisions. [ABSTRACT FROM AUTHOR]

Background: Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in human epidermal growth factor 2 (HER2)-negative early and metastatic breast cancer (BC). However, the prognostic and predictive value of serial TK1 activity in HER2-positive BC remains unknown. Methods: In the PREDIX HER2 trial, 197 HER2-positive BC patients were randomized to neoadjuvant trastuzumab, pertuzumab, and docetaxel (DPH) or trastuzumab emtansine (T-DM1), followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum samples were prospectively collected from all participants at multiple timepoints: at baseline, after cycle 1, 2, 4, and 6, at end of adjuvant therapy, annually for a total period of 5 years and/or at the time of recurrence. The associations of sTK1 activity with baseline characteristics, pathologic complete response (pCR), event-free survival (EFS), and disease-free survival (DFS) were evaluated. Results: No association was detected between baseline sTK1 levels and all the baseline clinicopathologic characteristics. An increase of TK1 activity from baseline to cycle 2 was seen in all cases. sTK1 level at baseline, after 2 and 4 cycles was not associated with pCR status. After a median follow-up of 58 months, 23 patients had EFS events. There was no significant effect between baseline or cycle 2 sTK1 activity and time to event. A non-significant trend was noted among patents with residual disease (non-pCR) and high sTK1 activity at the end of treatment visit, indicating a potentially worse long-term prognosis. Conclusion: sTK1 activity increased following neoadjuvant therapy for HER2-positive BC but was not associated with patient outcomes or treatment benefit. However, the post-surgery prognostic value in patients that have not attained pCR warrants further investigation. Trial registration: ClinicalTrials.gov, NCT02568839. Registered on 6 October 2015. [ABSTRACT FROM AUTHOR]

Purpose: Metronomic chemotherapy has the potential to offer tumor control with reduced toxicity when compared to standard dose chemotherapy in patients with metastatic breast cancer. As metronomic chemotherapy may target the tumor microvasculature, it has the potential for synergistic effects with antiangiogenic agents such as the VEGF-A inhibitor bevacizumab. Methods: In this randomized phase II study, patients with metastatic breast cancer were randomized to receive metronomic oral cyclophosphamide and methotrexate (CM) combined with bevacizumab (Arm A) or CM alone (Arm B). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety and tolerability. Results: A total of 55 patients were enrolled, with 34 patients treated on Arm A and 21 patients treated on Arm B. The ORR was modestly higher in Arm A (26%) than in Arm B (10%); neither met the 40% cutoff for further clinical evaluation. The median time to progression (TTP) was 5.52 months (3.22–13.6) on Arm A and 1.82 months (1.54–6.70) on Arm B (log-rank p = 0.008). The median OS was 29.6 months (17.2–NA) on Arm A and 16.2 months (15.7–NA) on Arm B (log-rank p = 0.7). Common all-grade adverse events in both arms included nausea, fatigue, and elevated AST. Conclusion: The combination of metronomic CM with bevacizumab significantly improved PFS over CM alone, although there was no significant difference in OS. Oral metronomic chemotherapy alone has limited activity in advanced breast cancer. ClinicalTrials.gov Identifier: NCT00083031. Date of Registration: May 17, 2004. [ABSTRACT FROM AUTHOR]

Background: Breast cancer chemotherapy utilization not only may differ by race and age, but also varies by genomic risk, tumor characteristics, and patient characteristics. Studies in demographically diverse populations with both clinical and genomic data are necessary to understand potential disparities by race and age. Methods: In the Carolina Breast Cancer Study Phase 3 (2008–2013), chemotherapy receipt (yes/no) and regimen type were assessed in association with age and race among hormone receptor (HR) positive and HER2-negative tumors (n = 1862). Odds ratios were estimated for the association between demographic factors and chemotherapy receipt. Results: Monotonic decreases in frequency of adjuvant chemotherapy receipt were observed over time during the study period, while neoadjuvant chemotherapy was stable. Younger age was associated with chemotherapy receipt (OR [95% CI]: 2.9 [2.4, 3.6]) and with anthracycline-based regimens (OR [95% CI]: 1.7 [1.3, 2.4]). Participants who had Medicaid (OR [95% CI]: 1.8 [1.3, 2.5]), lived in rural settings (OR [95% CI]: 1.4 [1.0, 2.0]), or were Black (OR [95% CI]: 1.5 [1.2, 1.8]) had slightly higher odds of chemotherapy, but these associations were non-significant with adjustment for stage and grade. Associations between younger age and chemotherapy receipt were strongest among women who did not receive genomic testing. Conclusions: While race was not strongly associated with chemotherapy receipt, younger age remains a strong predictor of chemotherapy receipt, even with adjustment for clinical factors and among women who receive genomic testing. [ABSTRACT FROM AUTHOR]

Purpose: Metronomic chemotherapy has the potential to offer tumor control with reduced toxicity when compared to standard dose chemotherapy in patients with metastatic breast cancer. As metronomic chemotherapy may target the tumor microvasculature, it has the potential for synergistic effects with antiangiogenic agents such as the VEGF-A inhibitor bevacizumab. Methods: In this randomized phase II study, patients with metastatic breast cancer were randomized to receive metronomic oral cyclophosphamide and methotrexate (CM) combined with bevacizumab (Arm A) or CM alone (Arm B). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety and tolerability. Results: A total of 55 patients were enrolled, with 34 patients treated on Arm A and 21 patients treated on Arm B. The ORR was modestly higher in Arm A (26%) than in Arm B (10%); neither met the 40% cutoff for further clinical evaluation. The median time to progression (TTP) was 5.52 months (3.22–13.6) on Arm A and 1.82 months (1.54–6.70) on Arm B (log-rank p = 0.008). The median OS was 29.6 months (17.2–NA) on Arm A and 16.2 months (15.7–NA) on Arm B (log-rank p = 0.7). Common all-grade adverse events in both arms included nausea, fatigue, and elevated AST. Conclusion: The combination of metronomic CM with bevacizumab significantly improved PFS over CM alone, although there was no significant difference in OS. Oral metronomic chemotherapy alone has limited activity in advanced breast cancer. ClinicalTrials.gov Identifier: NCT00083031. Date of Registration: May 17, 2004. [ABSTRACT FROM AUTHOR]

Background: Breast cancer chemotherapy utilization not only may differ by race and age, but also varies by genomic risk, tumor characteristics, and patient characteristics. Studies in demographically diverse populations with both clinical and genomic data are necessary to understand potential disparities by race and age. Methods: In the Carolina Breast Cancer Study Phase 3 (2008–2013), chemotherapy receipt (yes/no) and regimen type were assessed in association with age and race among hormone receptor (HR) positive and HER2-negative tumors (n = 1862). Odds ratios were estimated for the association between demographic factors and chemotherapy receipt. Results: Monotonic decreases in frequency of adjuvant chemotherapy receipt were observed over time during the study period, while neoadjuvant chemotherapy was stable. Younger age was associated with chemotherapy receipt (OR [95% CI]: 2.9 [2.4, 3.6]) and with anthracycline-based regimens (OR [95% CI]: 1.7 [1.3, 2.4]). Participants who had Medicaid (OR [95% CI]: 1.8 [1.3, 2.5]), lived in rural settings (OR [95% CI]: 1.4 [1.0, 2.0]), or were Black (OR [95% CI]: 1.5 [1.2, 1.8]) had slightly higher odds of chemotherapy, but these associations were non-significant with adjustment for stage and grade. Associations between younger age and chemotherapy receipt were strongest among women who did not receive genomic testing. Conclusions: While race was not strongly associated with chemotherapy receipt, younger age remains a strong predictor of chemotherapy receipt, even with adjustment for clinical factors and among women who receive genomic testing. [ABSTRACT FROM AUTHOR]

Everolimus is an orally available inhibitor of the mammalian target of rapamycin (mTOR), which has been approved in combination with exemestane for hormone receptor-positive (HR) breast cancer after failure of treatment with non-steroidal aromatase inhibitors. Everolimus is generally very well tolerated with most common side effects including stomatitis, rash, fatigue, hyperglycemia, hyperlipidemia, and myelosuppression. Most of these side effects are mild and resolve with dose interruptions or dose reductions. Symptomatic non-infectious pneumonitis is a relatively uncommon class effect of mTOR inhibitors, which can be life threatening. Given the efficacy of everolimus in HR-positive metastatic breast cancer, it is crucial for physicians to recognize toxicities related to everolimus and start timely interventions. This review will focus on the adverse events reported with everolimus in breast cancer trials and will provide practical guidelines for the management of these adverse events. [ABSTRACT FROM AUTHOR]

We sought to compare the molecular signature of node negative cancers from two cohorts 15 years apart, to determine if there is molecular evidence of increase in low and ultralow risk cancers over time. We studied the impact of age, time period of diagnosis, and mammographic screening on biology of tumors where The Netherlands Cancer Institute 70-gene prognosis signature was generated as part of 2 validation series, one retrospective (1984-1992), Cohort 1, and one prospective (2004-2006), Cohort 2. A total of 866 patients were analyzed. Regardless of time period of diagnosis, the proportion of T1, grade 1, hormone receptor positive (HR) tumors, and good prognosis by 70-gene signature significantly increases as age increases ( P < 0.01). In women aged 49-60, the time period of diagnosis significantly affects the proportion of cancers that were NKI 70-gene low risk: 40.6% (67/165) compared with 58% (119/205) for Cohorts 1 and 2, respectively. This is in contrast to the absence of a significant change for women under age 40, where 25% (17/68) and 30% (17/56) were low risk in Cohorts 1 and 2, respectively. In women aged 49-60, using an ultralow risk threshold of the 70-gene signature, 10% of tumors in Cohort 1 were ultralow risk compared with 30% for women with screen-detected cancers in Cohort 2. Older age and method of detection (screening) are associated with a higher likelihood of a biologically low risk tumor. In women over age 50, biologically low risk tumors are frequent and tools that classify risk may minimize overtreatment. [ABSTRACT FROM AUTHOR]

Purpose: This study determines the prognostic impact of body mass index (BMI) in patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2−) advanced (i.e., metastatic) breast cancer (ABC). Methods: All patients with HR+/HER2− ABC who received endocrine therapy +—a cyclin-dependent kinase 4/6 inhibitor as first-given systemic therapy in 2007–2020 in the Netherlands were identified from the Southeast Netherlands Advanced Breast Cancer (SONABRE) registry (NCT03577197). Patients were categorised as underweight (BMI: < 18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), or obese (≥ 30.0 kg/m2). Overall survival (OS) and progression-free survival (PFS) were compared between BMI classes using multivariable Cox regression analyses. Results: This study included 1456 patients, of whom 35 (2%) were underweight, 580 (40%) normal weight, 479 (33%) overweight, and 362 (25%) obese. No differences in OS were observed between normal weight patients and respectively overweight (HR 0.99; 95% CI 0.85–1.16; p = 0.93) and obese patients (HR 1.04; 95% CI 0.88–1.24; p = 0.62). However, the OS of underweight patients (HR 1.45; 95% CI 0.97–2.15; p = 0.07) tended to be worse than the OS of normal weight patients. When compared with normal weight patients, the PFS was similar in underweight (HR 1.05; 95% CI 0.73–1.51; p = 0.81), overweight (HR 0.90; 95% CI 0.79–1.03; p = 0.14), and obese patients (HR 0.88; 95% CI 0.76–1.02; p = 0.10). Conclusion: In this study among 1456 patients with HR+/HER2− ABC, overweight and obesity were prevalent, whereas underweight was uncommon. When compared with normal weight, overweight and obesity were not associated with either OS or PFS. However, underweight seemed to be an adverse prognostic factor for OS. [ABSTRACT FROM AUTHOR]

Purpose: The tumor-stroma ratio (TSR) is a common histological parameter that measures stromal abundance and is prognostic in breast cancer (BC). However, more evidence is needed on the predictive value of the TSR for the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). The purpose of this study was to determine the importance of the TSR in predicting pCR in NAC settings. Method: We evaluated the TSR on pretreatment biopsies of 912 BC patients from four independent Chinese hospitals and investigated the potential value of the TSR for predicting pCR. Meanwhile, stromal tumor-infiltrating lymphocytes (sTILs) were assessed, and we evaluated the predictive value of the combination of sTILs and TSR (TSRILs). Results: Patients with low stroma showed a higher pCR rate than those with high stroma among the four independent hospitals, and in multivariate analysis, the TSR was proven to be an independent predictor for pCR to NAC with an odds ratio of 1.945 (95% CI 1.230–3.075, P = 0.004). Moreover, we found that TSRILs could improve the area under the curve (AUC) for predicting pCR from 0.750 to 0.785 (P = 0.039); especially in HER2-negative BCs, the inclusion of TSRILs increased the AUC from 0.801 to 0.835 in the discovery dataset (P = 0.048) and 0.734 to 0.801 in the validation dataset (P = 0.003). Conclusion: TSR and sTILs can be easily measured in pathological routines and provide predictive information without additional cost; with more evidence from clinical trials, TSRILs could be a candidate to better stratify patients in NAC settings. [ABSTRACT FROM AUTHOR]

Purpose: In HER2-positive (HER2 +) breast cancer, tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may influence the efficacy of the HER2-antibody trastuzumab and the patient's outcome. In this HER2 + patient cohort, our aim was to study the numbers of FoxP3 + regulatory TILs and CD8 + cytotoxic TILs, their correlations with CD68 + and CD163 + TAMs, and the prognostic and predictive value of the studied factors. Methods: We evaluated 139 non-metastatic HER2 + breast cancer patients operated between 2001 and 2008. The FoxP3+TIL count (FoxP3+TILs) was assessed using the hotspot method, and the CD8 + TIL count (CD8+mTILs) utilizing a digital image analysis from invasive margin areas. The ratios between CD8+mTILs and FoxP3+TILs as well as CD8+mTILs and TAMs were calculated. Results: FoxP3 + TILs and CD8 + mTILs correlated positively with each other (p<0.001). FoxP3+TILs had a positive correlation with CD68+and CD163+TAMs (p≤0.038), while CD8 + mTILs correlated only with CD68+TAMs (p<0.001). In the HER2 + and hormone receptor-positive Luminal B subgroup, high numbers of FoxP3+TILs were associated with shorter disease-free survival (DFS) (54% vs. 79%, p = 0.040). The benefit from adjuvant trastuzumab was extremely significant among patients with a high CD8 + mTILs/CD68 + TAMs ratio, with overall survival (OS) 84% vs. 33% (p = 0.003) and breast cancer-specific survival (BCSS) 88% vs. 48% (p = 0.009) among patients treated with or without trastuzumab, respectively. Conclusion: In the HER2 + Luminal B subgroup, high FoxP3 + TILs were associated with shorter DFS. A high CD8 + mTILs/CD68 + TAMs ratio seems to associate with impressive efficacy of trastuzumab. [ABSTRACT FROM AUTHOR]

Introduction: In light of the clinically meaningful results of the PI3K inhibitors in PIK3CA-mutated metastatic breast cancer (BC) patients, the reliable identification of PIK3CA mutations is of outmost importance. However, lack of evidence on the optimal site and timing of assessment, presence of temporal heterogeneity and analytical factors pose several challenges in clinical routine. We aimed to study the discordance rates of PIK3CA mutational status between primary and matched metastatic tumors. Methods: A systematic literature search was performed in three different databases (Embase, Pubmed, Web of Science) and—upon screening—a total of 25 studies reporting PIK3CA mutational status both on primary breast tumors and their matched metastases were included in this meta-analysis. The random-effects model was used for pooled analyses of discordance of PIK3CA mutational status. Results: The overall discordance rate of PIK3CA mutational status was 9.8% (95% CI, 7.0–13.0; n = 1425) and did not significantly differ within BC subtypes or metastatic sites. The change was bi-directional, more commonly observed from PIK3CA mutated to wild-type status (14.9%, 95% CI 11.8–18.2; n tumor pairs = 453) rather than the opposite direction (8.9%, 95% CI 6.1–12.1; n tumor pairs = 943). Conclusions: Our results indicate the need of obtaining metastatic biopsies for PIK3CA-mutation analysis and the possibility of testing of the primary tumor, in case a re-biopsy deemed non-feasible. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to determine the pattern of isolated local recurrences (ILR) in women with stage II-III hormone receptor-positive and human epidermal growth factor receptor 2 breast cancer (HR + /HER2-BC) after 10-year follow-up. Methods: UNICANCER-PACS 01 and PACS 04 trials included 5,008 women with T1-T3 and N1-N3 to evaluate the efficacy of different anthracycline ± taxanes-containing regimens after modified mastectomy or lumpectomy plus axillary lymph node dissection. We analyzed the data from 2,932 women with HR + /HER2- BC to evaluate the cumulative incidence of ILR and describe the factors associated with ILR. Results: After a median follow-up of 9.1 years (95% CI 9.0–9.2 years), the cumulative incidence of ILR increased steadily between 1 and 10 years from 0.2% to 2.5%. The multivariable analysis showed that older age (subhazard ratios [sHR] = 0.95, 95% CI 0.92–0.99) and mastectomy (sHR = 0.39, 95% CI 0.17–0.86) were associated with lower risk of ILR, and no adjuvant endocrine therapy (sHR = 2.73, 95% CI 1.32 7–5.67) with increased risk of ILR. Conclusion: In this population of high-risk patients with localized HR + /HER2- BC, the risk of ILR was low but remained constant over 10 years. Younger age at diagnosis, breast-conserving surgery, and adjuvant endocrine therapy were independent risk factors of ILR. [ABSTRACT FROM AUTHOR]

Purpose: Neoadjuvant systemic therapy (NST) is increasingly used in breast cancer patients and depending on subtype, 10–89% of patients will attain pathologic complete response (pCR). In patients with pCR, risk of local recurrence (LR) after breast conserving therapy is low. Although adjuvant radiotherapy after breast conserving surgery (BCS) reduces LR further in these patients, it may not contribute to overall survival. However, radiotherapy may cause early and late toxicity. The aim of this study is to show that omission of adjuvant radiotherapy in patients with a pCR after NST will result in acceptable low LR rates and good quality of life. Methods: The DESCARTES study is a prospective, multicenter, single arm study. Radiotherapy will be omitted in cT1-2N0 patients (all subtypes) who achieve a pCR of the breast and lymph nodes after NST followed by BCS plus sentinel node procedure. A pCR is defined as ypT0N0 (i.e. no residual tumor cells detected). Primary endpoint is the 5-year LR rate, which is expected to be 4% and deemed acceptable if less than 6%. In total, 595 patients are needed to achieve a power of 80% (one-side alpha of 0.05). Secondary outcomes include quality of life, Cancer Worry Scale, disease specific and overall survival. Projected accrual is five years. Conclusion: This study bridges the knowledge gap regarding LR rates when adjuvant radiotherapy is omitted in cT1-2N0 patients achieving pCR after NST. If the results are positive, radiotherapy may be safely omitted in selected breast cancer patients with a pCR after NST. Trial registration: This study is registered at ClinicalTrials.gov on June 13th 2022 (NCT05416164). Protocol version 5.1 (15-03-2022). [ABSTRACT FROM AUTHOR]

Purpose: Few targeted treatment options currently exist for patients with advanced, often recurrent breast cancers, both triple-negative breast cancer (TNBC) and hormone receptor-positive breast cancer. Forkhead box M1 (FOXM1) is an oncogenic transcription factor that drives all cancer hallmarks in all subtypes of breast cancer. We previously developed small-molecule inhibitors of FOXM1 and to further exploit their potential as anti-proliferative agents, we investigated combining FOXM1 inhibitors with drugs currently used in the treatment of breast and other cancers and assessed the potential for enhanced inhibition of breast cancer. Methods: FOXM1 inhibitors alone and in combination with other cancer therapy drugs were assessed for their effects on suppression of cell viability and cell cycle progression, induction of apoptosis and caspase 3/7 activity, and changes in related gene expressions. Synergistic, additive, or antagonistic interactions were evaluated using ZIP (zero interaction potency) synergy scores and the Chou–Talalay interaction combination index. Results: The FOXM1 inhibitors displayed synergistic inhibition of proliferation, enhanced G2/M cell cycle arrest, and increased apoptosis and caspase 3/7 activity and associated changes in gene expression when combined with several drugs across different pharmacological classes. We found especially strong enhanced effectiveness of FOXM1 inhibitors in combination with drugs in the proteasome inhibitor class for ER-positive and TNBC cells and with CDK4/6 inhibitors (Palbociclib, Abemaciclib, and Ribociclib) in ER-positive cells. Conclusion: The findings suggest that the combination of FOXM1 inhibitors with several other drugs might enable dose reduction in both agents and provide enhanced efficacy in treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have improved HR + /HER2− metastatic breast cancer (MBC) outcomes. However, it is still unclear whether the response to CDK4/6i is similar for all races. Therefore, we aimed to assess overall survival (OS) trends stratified by race in patients with HR + /HER2− MBC after the approval of CDK4/6i, as part of the standard of care, in 2015. Methods: We performed a population-based study using the SEER database. Patients with HR + /HER2− MBC were divided into two time-based cohorts: 1) pre-CDK4/6i era (diagnosed in 2011–2013) and 2) post-CDK4/6i era (diagnosed in 2015–2017). We used propensity score matching and identified 2,684 patients in each cohort that matched in several characteristics. Kaplan–Meier methods were used to estimate 2-year OS. Association between cohort and OS was evaluated using marginal Cox proportional hazards models with robust sandwich variance estimator. We conducted competing risk analysis to estimate the risk of breast cancer death in both cohorts. Results: The 2-year OS rate was 65% for the post-CDK4/6i era and 62% for the pre-CDK4/6i era (stratified log-rank p = 0.025). The 2-year OS for non-Hispanic White (NHW) patients improved in the post-CDK4/6i era compared to the pre-CDK4/6i era (67% vs. 63%, p = 0.033). However, OS did not improve for non-Hispanic Black (NHB) (54% vs. 54%, p = 0.876) or Hispanic (67% vs. 65%, p = 0.617) groups. The risk of breast cancer death decreased in the post-CDK4/6i era as compared to the pre-CDK4/6i era (2-year risk of breast cancer death: 33% vs. 30%, p = 0.015); however, this effect was observed only in NHW (sHR 0.84, p = 0.005) women, but not in NHB (sHR 0.94, p = 0.630) or Hispanic (sHR 0.91, p = 0.550) women. Conclusions: Our study confirms that outcomes for HR + /HER2− MBC have improved after CDK4/6i were introduced in 2015. However, this effect is primarily driven by the improved OS in NHW patients, without significant improvement in OS in NHB or Hispanics. [ABSTRACT FROM AUTHOR]

Purpose: CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have improved HR + /HER2− metastatic breast cancer (MBC) outcomes. However, it is still unclear whether the response to CDK4/6i is similar for all races. Therefore, we aimed to assess overall survival (OS) trends stratified by race in patients with HR + /HER2− MBC after the approval of CDK4/6i, as part of the standard of care, in 2015. Methods: We performed a population-based study using the SEER database. Patients with HR + /HER2− MBC were divided into two time-based cohorts: 1) pre-CDK4/6i era (diagnosed in 2011–2013) and 2) post-CDK4/6i era (diagnosed in 2015–2017). We used propensity score matching and identified 2,684 patients in each cohort that matched in several characteristics. Kaplan–Meier methods were used to estimate 2-year OS. Association between cohort and OS was evaluated using marginal Cox proportional hazards models with robust sandwich variance estimator. We conducted competing risk analysis to estimate the risk of breast cancer death in both cohorts. Results: The 2-year OS rate was 65% for the post-CDK4/6i era and 62% for the pre-CDK4/6i era (stratified log-rank p = 0.025). The 2-year OS for non-Hispanic White (NHW) patients improved in the post-CDK4/6i era compared to the pre-CDK4/6i era (67% vs. 63%, p = 0.033). However, OS did not improve for non-Hispanic Black (NHB) (54% vs. 54%, p = 0.876) or Hispanic (67% vs. 65%, p = 0.617) groups. The risk of breast cancer death decreased in the post-CDK4/6i era as compared to the pre-CDK4/6i era (2-year risk of breast cancer death: 33% vs. 30%, p = 0.015); however, this effect was observed only in NHW (sHR 0.84, p = 0.005) women, but not in NHB (sHR 0.94, p = 0.630) or Hispanic (sHR 0.91, p = 0.550) women. Conclusions: Our study confirms that outcomes for HR + /HER2− MBC have improved after CDK4/6i were introduced in 2015. However, this effect is primarily driven by the improved OS in NHW patients, without significant improvement in OS in NHB or Hispanics. [ABSTRACT FROM AUTHOR]

Purpose: SOLAR-1 investigated alpelisib-fulvestrant (ALP + FLV) in patients with HR + /HER2-, PIK3CA-mutated advanced breast cancer and demonstrated a clinically significant increase in all-grade and grade (G) 3-4 hyperglycemia (HG) compared to placebo-fulvestrant. Given high rates of HG, a preventative protocol and identification of associated risk factors was implemented. Methods: This single-center, retrospective study included patients receiving ALP + FLV. One week before ALP initiation, patients started an insulin-sensitizer. Patients had fasting plasma glucose (FPG) levels drawn day 8, 15, 28, then monthly. Primary outcome was incidence of G2-4 HG by day 28. Risk factors assessed included age, BMI, FPG, and HbA1c. Number of risk factors were compared between patients with and without HG. Results: Sixteen women were included with median age of 59 years. The cohort was 69% White, 25% Black, 75% with BMI ≥ 25 kg/m2, and 50% with history of diabetes. By day 28, 9 patients (56%) had G2-4 HG, with only 3 (19%) G3 and zero G4. Patients with G2-4 HG had a median of 2 risk factors compared to only 1 if no HG (p = 0.03). 5 patients (31%) required a temporary hold of ALP and 3 (19%) required dose reduction due to HG. 13 patients permanently discontinued ALP—9 due to disease progression and 4 from an adverse event (only 1 HG). Conclusion: Implementation of a HG prophylaxis protocol with ALP in a single-center study demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (19% vs 36.6%). An increase in HG-associated risk factors correlated with a higher incidence of G2-4 HG. [ABSTRACT FROM AUTHOR]

Purpose: GDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling. Methods: A phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 −) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status. Results: Patients (N = 152) received GDC-0810 100–800 mg once daily (QD) or 300–400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%). Conclusion: GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835. [ABSTRACT FROM AUTHOR]

Purpose: Sexual function problems are common but under-reported among women receiving adjuvant endocrine therapy for breast cancer. Worsening scores on patient-reported outcomes (PROs) may identify those at risk for sexual function problems during treatment. We performed a secondary analysis of prospectively collected PROs in women receiving adjuvant endocrine therapy to identify factors associated with worsening sexual function. Methods: Women with stage 0–III breast cancer initiating adjuvant endocrine therapy participating in a prospective cohort completed PROs at baseline, 3, 6, 12, 24, 36, 48, and 60 months. Sexual function was evaluated by the MOS-SP measure. Other measures included PROMIS pain interference, fatigue, depression, anxiety, physical function, and sleep disturbance and the Endocrine Symptom Subscale of the FACT-ES. We evaluated associations between score worsening of at least the minimal important difference (MID) in PROMIS T-scores (4 points) and FACT-ES scores (5 points) with score worsening of at least the MID in MOS-SP scores (8 points) using logistic regression. Results: Among 300 participants, 45.7% experienced ≥ 8-point worsening of MOS-SP score at any time point compared to baseline. Worsening endocrine symptoms (OR 1.34, 95% CI 1.22–1.49, p < 0.001), worsening physical function (OR 1.09, 95% CI 1.00–1.18, p = 0.06), and prior mastectomy (OR 1.45, 95% CI 0.94–2.23, p = 0.09) were associated with MOS-SP score worsening by at least the MID. Conclusion: Worsening endocrine symptoms and physical function identified on PROs are associated with worsening sexual function during adjuvant endocrine therapy. Routine assessment of these domains with PROs may identify women at risk for sexual function problems. Trial registration number: NCT01937052; Date of Registration: 09/09/2013. [ABSTRACT FROM AUTHOR]

Purpose: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in early breast cancer (EBC) is largely dependent on breast cancer subtype, but no clinical-grade model exists to predict response and guide selection of treatment. A biophysical simulation of response to NAC has the potential to address this unmet need. Methods: We conducted a retrospective evaluation of a biophysical simulation model as a predictor of pCR. Patients who received standard NAC at the University of Chicago for EBC between January 1st, 2010 and March 31st, 2020 were included. Response was predicted using baseline breast MRI, clinicopathologic features, and treatment regimen by investigators who were blinded to patient outcomes. Results: A total of 144 tumors from 141 patients were included; 59 were triple-negative, 49 HER2-positive, and 36 hormone-receptor positive/HER2 negative. Lymph node disease was present in half of patients, and most were treated with an anthracycline-based regimen (58.3%). Sensitivity and specificity of the biophysical simulation for pCR were 88.0% (95% confidence interval [CI] 75.7 – 95.5) and 89.4% (95% CI 81.3 – 94.8), respectively, with robust results regardless of subtype. In patients with predicted pCR, 5-year event-free survival was 98%, versus 79% with predicted residual disease (log-rank p = 0.01, HR 4.57, 95% CI 1.36 – 15.34). At a median follow-up of 5.4 years, no patients with predicted pCR experienced disease recurrence. Conclusion: A biophysical simulation model accurately predicts pCR and long-term outcomes from baseline MRI and clinical data, and is a promising tool to guide escalation/de-escalation of NAC. [ABSTRACT FROM AUTHOR]

Purpose: Metformin has demonstrated a chemoprotective effect in breast cancer but there is limited evidence on the effect of cumulative exposure to metformin and the risk of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + /HER2-) breast cancer. This study assessed this risk with dose and intensity of metformin in postmenopausal women with type-2 diabetes mellitus (T2DM). Methods: This nested case–control study used the Surveillance, Epidemiology, and End Results-Medicare data (2008–2015). Cohort entry was the date of incident T2DM diagnosis. Cases were those diagnosed with HR + /HER2- breast cancer (event date) as their first/only cancer. Non-cancer T2DM controls were matched using variable-ratio-matching. Cumulative dose and average intensity of metformin were measured during the 1-year lookback period. Dose(mg) was categorized as: (1)0, (2)0–30,000, (3)30,001–136,000, (4)136,001–293,000, and (5) > 293,000, and intensity(mg/day) as: 0, 1–500, and > 500. Covariates were conceptualized using the Andersen Behavioral Model. Conditional logistic regression was used to assess the risk of HR + /HER2- breast cancer with metformin-use. Results: There were 690 cases and 2747 controls. The median duration of T2DM was 1178 days in controls and 1180 days in cases. Higher cumulative dose categories: 4 (adjusted odds ratio(aOR) = 0.72, 95% CI 0.55–0.95,p = 0.02), and 5 (OR = 0.60, 95% CI 0.42–0.85,p < 0.01) had significantly lower odds of HR + /HER2- breast cancer compared to category 0. The highest intensity category of metformin had 39% lower odds of HR + /HER2- breast cancer (OR = 0.61, 95% CI 0.46–0.82,p < 0.01) compared to the 0 mg/day group. Conclusions: Higher metformin exposure was associated with reduced risk of HR + /HER2- breast cancer, adding to the evidence supporting metformin's chemoprotective effect. [ABSTRACT FROM AUTHOR]

Purpose: Abemaciclib, a CDK4 & 6 inhibitor, is indicated for advanced breast cancer treatment. Diarrhea is a frequently associated adverse event of abemaciclib. The study objective was to investigate if food intake impacts local gastrointestinal toxicity. Methods: This Phase 2 study (I3Y-MC-JPCP, NCT03703466) randomized 72 patients 1:1:1 to receive abemaciclib 200 mg monotherapy twice daily (1) with a meal, (2) in a modified fasting state or (3) without regard to food. Primary endpoints included: incidence of investigator assessed severe (≥ Grade 3), prolonged (> 7 days) Grade 2 diarrhea, treatment discontinuation, dose modifications, and loperamide utilization during the first 3 cycles of treatment. Patient outcomes were captured via a daily electronic diary. Pharmacokinetics (PK) are reported. Results: Incidence of investigator assessed severe diarrhea (Grade ≥ 3) was 1.4% (1 patient in Arm 1). Median duration of Grade 3 diarrhea was 1 day by both investigator assessment (1 patient in Arm 1) and patient-reported assessment (1 patient each in Arms 1 and 3). Median duration of investigator-assessed Grade 2 diarrhea was 2 days overall. No patient discontinued treatment due to diarrhea. Nine patients (12.7%) had a dose reduction, and 7 patients (9.9%) had a dose omission due to diarrhea. Ninety-four percent of patients used loperamide at least once. Abemaciclib PK was comparable across the 3 arms. Conclusion: The results suggest that diarrhea incidence associated with abemaciclib was unrelated to timing of food intake, was predominantly low grade, of short duration and well managed with loperamide and dose modifications. [ABSTRACT FROM AUTHOR]

The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR), human epidermal growth factor receptor-2-negative (HER2) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE ( n = 100) or PBO + EXE ( n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25-0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18-0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR, HER2 advanced breast cancer in postmenopausal patients. [ABSTRACT FROM AUTHOR]

Purpose: Genomic profiling in early-stage breast cancer provides prognostic and predictive information. Genomic profiling assays have not been validated in locally advanced breast cancer (LABC). We examined a large cancer registry to evaluate genomic profiling in LABC and its effect on treatment decisions and survival. Methods: Females with ER+/HER2− LABC who did not receive neoadjuvant therapy were selected from the National Cancer Database 2004–2017. We compared characteristics between patients with and without genomic profiling and with low genomic risk, 21-gene recurrence score ≤ 25 or low-risk 70-gene signature, treated with endocrine therapy ± chemotherapy. Propensity score methods were utilized to account for covariates that may have predicted treatment. Univariable and multivariable survival analyses were performed. Results: Of 18,437 patients with LABC, 1258 (7%) had genomic profiling and 1022 (81%) had low genomic risk results. 562 patients (55%) with low genomic risk received chemotherapy and endocrine therapy (chemoendocrine). Patients who received chemoendocrine therapy were younger, had fewer comorbidities, presented with higher stage disease, had higher grade tumors, more frequently had partial mastectomy, and more often received radiation than those who received endocrine therapy alone. On multivariable analysis, endocrine therapy alone was associated with worse OS compared to chemoendocrine therapy (HR 1.77, 95% CI 1.13–2.78, p = 0.013). Conclusion: In women with LABC and low genomic risk, endocrine therapy alone was associated with worse OS compared to chemoendocrine therapy. This suggests that genomic profiling is not predictive in LABC. Accordingly, genomic profiling should not be routinely utilized to make adjuvant treatment decisions in LABC in the absence of further data which shows a benefit. [ABSTRACT FROM AUTHOR]

Purpose: This study assessed chemotherapy use trends before (neoadjuvant chemotherapy [NAC]) or after surgery (adjuvant chemotherapy [AdC]) among older women with breast cancer and examined factors related to NAC receipt. Methods: Women (> 65 years) diagnosed with stage I–III breast cancer during 2010–2017 who received NAC or AdC were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. All patients were stratified into six strata based on subtype (hormone receptor-positive/human epidermal growth factor receptor 2-negative [HR + /HER2–], HER2 + , and triple-negative breast cancer [TNBC]) and stage (I–II and III). Cochran-Armitage tests were performed to test temporal trends of NAC use in each stratum. Multivariable logistic regression analyses were performed to identify factors (sociodemographic and clinical) related to NAC use. Results: Among included older (mean ± standard deviation: 72.3 ± 5.2 years) women (N = 8,495) with stage I–III breast cancer, NAC use increased from 11.7% (2010) to 32.6% (2017). Significant increases in NAC were found in all strata (p <.0001) with more substantial increases in HER2 + disease and TNBC compared to HR + /HER2– disease. Multivariable logistic regressions identified the youngest age category (66–69 years) and later stage as significant (p < 0.05) predictors of NAC receipt in most strata, in addition to diagnosis year. Conclusion: Similar to the overall breast cancer population, NAC use increased among a population of older women. NAC was received by most patients with stage III HER2 + disease or TNBC in more recent years and was more common among younger elderly women and those in stage III. [ABSTRACT FROM AUTHOR]

Abstract Background  In the primary core analysis of BIG 1–98, a randomized, double-blind trial comparing 5 years of initial adjuvant therapy with letrozole versus tamoxifen in postmenopausal women with hormone receptor-positive (HR) early breast cancer, letrozole significantly improved disease-free survival by 19% and reduced the risk of breast cancer recurrence by 28% and distant recurrence by 27%. Methods  A Markov model was used to estimate the incremental cost per quality-adjusted life year (QALY) gained with 5 years of initial adjuvant therapy with letrozole versus tamoxifen from a Canadian healthcare system perspective. Probabilities of recurrence and side effects for tamoxifen were based on published results of BIG 1–98 and other published population-based studies. Corresponding probabilities for letrozole were calculated by multiplying probabilities for tamoxifen by estimated relative risks for letrozole versus tamoxifen from BIG 1–98. Other probabilities, costs of breast-cancer care and treatment of side effects, and health-state utilities were obtained from published studies. Costs and QALYs were estimated over the lifetime of a cohort of postmenopausal women with HR early breast cancer, aged 60 years at initiation of therapy, and discounted at 5% annually. Results  Compared with tamoxifen, letrozole yields an additional 0.368 life-years (12.453 vs. 12.086) and 0.343 QALYs (11.582 vs. 11.239). These benefits are obtained at an additional cost of $Can 8,110 ($Can 30,819 vs. $Can 22,709). Cost per QALY gained for letrozole versus tamoxifen is $Can 23,662 (95% CI $Can 15,667–$Can 52,014). Conclusion  In postmenopausal women with HR early breast cancer, initial adjuvant treatment with letrozole is cost-effective from the Canadian healthcare system perspective. [ABSTRACT FROM AUTHOR]

Abstract Background  This study evaluated the cost-effectiveness of anastrozole versus generic tamoxifen for primary adjuvant treatment of postmenopausal women with hormone receptor-positive (HR) early breast cancer (EBC), from a US healthcare perspective. Methods  A probabilistic Markov model was developed using the 5-year completed treatment analysis of the ATAC (‘Arimidex’, Tamoxifen Alone or in Combination) trial (ISRCTN 18233230) to project outcomes for anastrozole and tamoxifen to 25 years. Resource utilization data were obtained primarily from published literature and a physician survey (including expert opinion from ATAC Steering Committee members). Drug costs were taken from published wholesale acquisition costs (anastrozole $6.56/day, generic tamoxifen $1.33/day). Other unit costs ($US 2003–4) were from standard sources. Utility estimates of relevant health states, used to compute quality-adjusted life-years (QALYs), were collected using the standard gamble technique in a cross-sectional sample of 44 patients. Costs and benefits were discounted 3% annually. Results  In a cohort of 1000 postmenopausal women with HR EBC, the model showed anastrozole treatment (versus tamoxifen) would lead to 257 QALYs gained (0.26 QALYs gained per patient), at an additional cost of $5.21 million over 25 years ($5,212 per patient). The estimated incremental cost-effectiveness ratio (ICER) of anastrozole compared with tamoxifen was $20,246 per QALY gained ($23,541 per life-year gained). Cost-effectiveness acceptability curves indicated a >90% probability that the cost per QALY gained with anastrozole would be Conclusion  Anastrozole is a cost-effective alternative to tamoxifen for the primary adjuvant treatment of postmenopausal women with HR EBC. [ABSTRACT FROM AUTHOR]

Abstract  Neoadjuvant chemotherapy trials have consistently reported lower response rates in hormone receptor-positive (HR) breast cancer when compared with HR− cases. Preoperative endocrine therapy has therefore become a logical alternative and has gained considerable momentum from the finding that aromatase inhibitors (AIs) are more effective than tamoxifen for HR breast cancer in both the neoadjuvant and adjuvant settings. The most convincing neoadjuvant trial to demonstrate the superiority of an AI versus tamoxifen was the P024 study, a large multinational double-blind trial in postmenopausal women with HR breast cancer ineligible for breast-conserving surgery. The overall response rate (ORR) was 55% for letrozole and 36% for tamoxifen (P P = 0.022). In addition, ORR was significantly higher with letrozole than tamoxifen in the human epidermal growth factor receptor HER1/HER2 subgroup (P = 0.0004). The clinical efficacy of letrozole in HER2 breast cancer was confirmed by fluorescent in situ hybridization analysis and was found to be comparable to that of HER2− cases (ORR 71% in both subsets). Biomarker studies confirmed the superiority of letrozole in centrally assessed estrogen receptor-positive (ER) tumors and found a strong relationship with the degree of ER positivity for both agents. Interestingly, letrozole was effective even in marginally ER tumors and, unlike tamoxifen, consistently reduced the expression from estrogen-regulated genes (progesterone receptor and trefoil factor 1). Furthermore, when analyzed by Ki67 immunohistochemistry, letrozole was significantly more effective than tamoxifen in reducing tumor proliferation (P = 0.0009). Thus, neoadjuvant letrozole is safe and superior to tamoxifen in the treatment of postmenopausal women with HR locally advanced breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer in men (BC-M) is almost exclusively hormone receptor positive. We conducted a large review of the SEER-Medicare linked database to compare endocrine therapy adherence, discontinuation, and survival outcomes of male versus female patients with breast cancer. Methods: Study data were obtained through the SEER-Medicare linked database. The study included patients age ≥ 65 years-old diagnosed with breast cancer between 2007 and 2015. The primary endpoints were rates of adherence and discontinuation of endocrine therapy (ET). Adherence was defined as a gap of less than 90 days in-between consecutive Medicare prescriptions. Discontinuation was defined as a gap of greater than 12 months in-between Medicare prescriptions. Secondary endpoint was the association of use of ET with overall survival (OS). Results: Of the 363 male patients on ET, 214 patients (59.0%) were adherent to the therapy, and 149 patients (41.0%) were nonadherent. Of the 20,722 females on ET, 10,752 (51.9%) were adherent to the therapy, and 9970 (48.1%) were nonadherent. 39 male patients (10.7%) discontinued therapy, while 324 (89.3%) did not discontinue therapy. 1849 female patients (8.9%) discontinued therapy, while 18,873 (91.1%) patients did not. Men were significantly more adherent than women (p = 0.008), but there was no significant difference in discontinuation among men and women (p = 0.228). Survival was significantly improved in both men (HR 0.77, 95% CI 0.60–0.99, p = 0.039) and women (HR 0.84, 95% CI 0.81–0.87, p < 0.001) on ET. Conclusion: Identification of contributing factors impacting adherence and discontinuation is needed to allow physicians to address barriers to long term use of ET. [ABSTRACT FROM AUTHOR]

Purpose: Despite advances in adjuvant therapeutic strategies, many patients with hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC) experience disease recurrence, even many years after primary surgery. The aim of this review is: (i) to point out the current clinical, pathological, and genomic features that contribute to define the risk of recurrence in HR-positive EBC, (ii) to explore the potential role of liquid biopsy-based assays for refining risk assessment, and (iii) to discuss future perspectives and innovative strategies to optimize risk stratification and select patients for treatment escalation. Methods: We searched PubMed, EMBASE and Scopus to review the current evidence about risk stratification in patients with HR-positive EBC, and to identify studies deemed to have the highest scientific value. Results: Risk stratification of HR-positive/HER2-negative relies on traditional clinicopathological features (age, menopausal status, tumor size, nodal status, tumor grading, HR expression level, and proliferation markers), along with newly developed genomic scores, which accurately predict risk of recurrence and survival. Multiparametric scores including both clinicopathological and genomic variables have the highest prognostication power, even if comparative studies have not defined which one should be preferred. In parallel, liquid biopsy-based showed to be a valuable tool to identify high risk patients. Conclusion: The most appropriate definition of "high" and "low" risk HR-positive EBC is still unclear. Accordingly, treatment escalation/de-escalation depending on recurrence risk remains challenging. Implementation of new tools for risk stratification, such as liquid biopsy-based assays, as well as development of novel treatment strategies are strongly warranted. [ABSTRACT FROM AUTHOR]

Purpose: Most studies of adherence to treatment for breast cancer have focused on early-stage patients. Findings from these studies may not generalize to patients with metastatic breast cancer (MBC). The objective of this study was to identify barriers and facilitators of adherence to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors among patients with MBC, guided by the social ecologic model (SEM). Methods: Patients with MBC (N = 25), their caregivers (N = 9), and oncology providers (N = 13) completed semi-structured qualitative interviews exploring their experiences with CDK4/6 inhibitors. Interviews were audio-recorded, transcribed verbatim, and analyzed by three raters using a combined deductive and inductive approach. Results: Qualitative analysis identified barriers and facilitators of adherence at each SEM level. Intrapersonal and interpersonal factors were most frequently discussed. Intrapersonal factors included knowledge/beliefs about CDK4/6 inhibitors, side effects, and establishing a routine. Interpersonal factors included effective communication with/coordination by the care team, support from family and friends, and information from other patients with MBC. Although less frequently discussed, policy factors (i.e., cost of CDK4/6 inhibitors) were of great concern to patients, caregivers, and providers. Conclusion: Barriers to adherence to CDK4/6 inhibitors exist at multiple levels. Our results underscore the potential value of a multilevel intervention (e.g., patient education, evidence-based strategies for symptom management, tips for open and assertive communication with providers, information about financial resources/support available, and so on) to support adherence in this population. [ABSTRACT FROM AUTHOR]

Purpose: Alpelisib is a phosphoinositide-3-kinase inhibitor approved for hormone-receptor-positive, PIK3CA-mutated metastatic breast cancer. However, length of drug exposure, maximum-tolerated dose, and therefore clinical response can vary significantly outside of the trial setting. This study evaluates our center's "real world" experience with alpelisib and focuses on duration of therapy and factors associated with cancer progression. Methods: Patients receiving alpelisib at our center between 2019 and 2021 were identified. We evaluated duration of alpelisib therapy and the causative reasons for drug discontinuation. The association of drug duration and dose with subsequent cancer progression were assessed, along with the association between hyperglycemia during alpelisib therapy and cancer progression. Results: Sixty-two women prescribed alpelisib were included (mean age 61 years). Disease progression was the most common reason for drug discontinuation, while discontinuation within 30 days was primarily attributed to adverse events (AEs). Among those who progressed, median time to progression was longer in those on alpelisib for > 90 days compared with those on alpelisib for ≤ 90 days (187 vs. 77 days, p < 0.001). At 200 days, freedom from progression was greater for those on alpelisib for > 90 days compared to those receiving therapy for ≤ 90 days (59% vs. 19%, p = 0.001). Median blood glucose as a continuous variable was associated with disease progression (HR 1.01, 95% CI 1.00–1.02, p = 0.02). Conclusion: While progression of disease is the largest contributor to alpelisib discontinuation, AEs are the leading cause for early drug cessation. Shorter alpelisib exposure is associated with greater cancer progression. Further studies are needed to determine the impact of sustained hyperglycemia on cancer progression. [ABSTRACT FROM AUTHOR]

Purpose: To examine benefit of sulindac for relief of musculoskeletal symptoms (MSS) in patients stable on aromatase inhibitors (AIs). Methods: Sulindac was evaluated at 150 mg twice daily for effects on MSS at 3, 6, 9, and 12 months in 50 postmenopausal women stable on AI therapy for a median of 12.5 months for hormone receptor-positive breast cancer. A separate, non-randomized group of 50 similar patients was observed for change in MSS over 12 months. MSS severity was assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Brief Pain Inventory Short Form (BPI-SF). The Functional Assessment of Cancer Therapy—General form (FACT-G) measured quality of life (QOL). Change in MSS and QOL across time was assessed in each group using linear mixed effects models. Results: Stiffness, not pain, was the main complaint at baseline. At 12 months, sulindac patients reported decreases (improvements) in mean (95% CI) Total WOMAC score [− 5.85 (− 9.73, − 1.96)] and WOMAC pain [− 5.40 (− 10.64, − 0.18)], Stiffness [− 9.53 (− 14.98, − 4.08)] and Physical Function [− 5.61 (− 9.62, − 1.60)] subscales, but not BPI-SF worst pain. Among sulindac patients with higher baseline MSS severity, 35% experienced ≥ 50% improvement in Total WOMAC and Total FACT-G scores [6.18 (2.08, 10.27); P = 0.003]. For the observation group, MSS and QOL did not improve over 12 months, even among those with higher baseline MSS severity. Conclusions: Sulindac may relieve MSS in AI patients, especially physical function and stiffness. Randomized controlled trials should further evaluate NSAIDs on AI-MSS and AI adherence. Trial registration number and date of registration: NCT01761877, December, 2012. [ABSTRACT FROM AUTHOR]

Purpose: There remain a lack of biomarkers for endocrine therapy resistance in patients with breast cancer (BC), which is proving to be a great challenge. In vitro experiments have shown that downregulation of PTEN expression leads to resistance to tamoxifen (TAM) in BC cells. We aimed to investigate the predictive role of tumor PTEN promoter methylation and PTEN expression in long-term survival after TAM adjuvant therapy in patients with early-stage BC. Methods: From 2001 to 2013, 105 patients with stage I–III BC who were treated with standardized adjuvant TAM for 5 years or until relapse in West China Hospital (WCH) were enrolled in this study. PTEN expression and DNA methylation of three specified sequences from the PTEN promoter in primary tumors were measured using immunohistochemistry and pyrosequencing. A cohort of 159 hormone receptor-positive patients receiving TAM treatment from The Cancer Genome Atlas (TCGA) database was used for verification. Results: Median follow-up time for the WCH cohort was 141.7 months. The low, moderate, and high PTEN expression groups had differing 10-year disease-free survival (DFS) (42.3%, 55%, 81%, respectively, P = 0.027) and overall survival (OS) rates (65%, 84.2%, 90.5%, respectively, P = 0.027). Higher methylation levels of the second sequence (− 819 to − 787 bp), rather than the first (− 1143 to − 1107 bp) or third sequence (− 663 to − 593 bp), independently increased the risk of disease recurrence (hazard ratio = 2.60) and death (hazard ratio = 3.79) in the WCH cohort, according to multivariate Cox regression analysis. Importantly, out of the five CpG islands located within this sequence, only high methylation of the − 796 CpG island predicted shorter DFS and OS. In TCGA validation cohort, there was also a trend of higher methylation of the − 796 CpG island correlating with shorter disease-free intervals, with borderline significance (P = 0.057). Conclusion: Low PTEN expression and high methylation of its promoter (sequence − 819 to − 787 bp) in tissue predict poor DFS and OS in hormone receptor-positive early BC patients who received adjuvant TAM. [ABSTRACT FROM AUTHOR]

Purpose: Symptoms of treatment-induced menopause negatively affect quality of life and adherence to endocrine therapy of breast cancer (BC) survivors. Nevertheless, the use of systemic hormone replacement therapy (HRT) to mitigate these symptoms may be associated with an increased risk of disease recurrence in these patients. This systematic review and meta-analysis aimed to assess the safety of systemic HRT on risk of disease recurrence in BC survivors. Methods: A systematic search of PubMed up to April 20, 2021 was conducted to identify randomized controlled trials (RCTs) that investigated the risk of disease recurrence with the use of HRT in BC survivors. A random-effect model was applied to calculate the risk of recurrence, reported as pooled hazard ratio (HR) with 95% confidence intervals (CI). A subgroup analysis was performed to estimate the risk of recurrence according to hormone receptor status. Results: Four RCTs were included in the meta-analysis (n = 4050 patients). Overall, 2022 patients were randomized to receive HRT (estrogen/progestogen combination or tibolone) and 2023 to the control group with placebo or no HRT. HRT significantly increased the risk of BC recurrence compared to placebo (HR 1.46, 95% CI 1.12–1.91, p = 0.006). At the subgroup analysis, the risk of BC recurrence with the use of HRT was significantly increased in patients with hormone receptor-positive disease (HR 1.8, 95% CI 1.15–2.82, p = 0.010) but not in those with hormone receptor-negative tumors (HR 1.19, 95% CI 0.80–1.77, p = 0.390). Conclusion: Use of HRT was associated with a detrimental prognostic effect in BC survivors, particularly in those with hormone receptor-positive disease. Alternative interventions to mitigate menopause-related symptoms should be proposed. [ABSTRACT FROM AUTHOR]

Purpose: A major question when treating HR+/HER2− metastatic breast cancer (MBC) is whether early introduction of chemotherapy (CT) increases endocrine resistance. We aimed to describe progression-free survival (PFS) under first endocrine therapy (ET) depending on whether given before or after CT in a large nationwide cohort, in the pre-CDK era. Methods: The real-life retrospective ESME database includes all patients with MBC whose first-line treatment was initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. Our primary objective was to compare PFS from start of first ET in patients with HR+/HER2− MBC who received ET or CT first. Results: We identified 6293 patients who received at least one ET line during their first two therapeutic lines for MBC. As first-line therapy, 3832 (60.9%) received ET alone (ET1 1st group), whilst 2461 (39.1%) received CT, including 2024 patients (32.2%) with maintenance ET after CT (ET1 after CT group). Median PFS under first ET was 12.4 months (95% CI 11.9–13.1) in ET 1st group vs. 12.6 months in ET1 after CT group (95% CI 12.1–13.4), HR 0.96 (95% CI 0.90–1.01, P = 0.1277). Conclusions: PFS under first ET appears identical whether prescribed before or after chemotherapy. These data suggest chemotherapy does not promote endocrine resistance. [ABSTRACT FROM AUTHOR]

Purpose: The most appropriate therapy for HR + /HER2-positive (HER2 +) advanced breast cancer (ABC) is a matter of debate. Co-targeting of both receptors represents an attractive strategy to overcome the cross-talk between them. Methods: The HERMIONE 9 is an observational retrospective multicentric study which aimed to describe the clinical outcome of patients with HR + /HER2 + ABC who received the combination of Fulvestrant (F) and Trastuzumab (T) as part of their routine treatment at 10 Italian Institutions. Results: Eighty-seven patients were included. Median age was 63 (range, 35–87) years. The median number of previous treatments was 3 (range, 0–10) and F and T were administered as ≥ 3rd line in 67 patients. Among the 86 evaluable patients, 6 (6.9%) achieved CR, 18 (20.7%) PR, and 44 (50.6%) had SD ≥ 24 weeks with an overall CBR of 78.2%. At a median follow-up of 33.6 months, mPFS of the entire cohort was 12.9 months (range, 2.47–128.67). No difference was observed in mPFS between patients treated after progression or as maintenance therapy (mPFS 12.9 and 13.9 months in 64 and 23 patients, respectively), neither considering the number of previous treatment lines (≤ 3 or < 3). Conclusion: The combination of F and T was active in this cohort at poor prognosis and deserves further investigations possibly in combination with pertuzumab in patients with high ER expression. [ABSTRACT FROM AUTHOR]