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Purpose: Everolimus in combination with endocrine therapy (ET) was formerly approved as 2nd-line therapy in HR(+)/HER2(−) advanced breast cancer (aBC) patients (pts) progressing during or after a non-steroidal aromatase inhibitor (NSAI). Since this approval, the treatment landscape of aBC has changed dramatically, particularly with the arrival of CDK 4–6 inhibitors. Endocrine monotherapy after progression to CDK4/6 inhibitors has shown a limited progression-free survival (PFS), below 3 months. Evidence of the efficacy of everolimus plus ET after CDK4/6 inhibitors is scarce. Methods: A retrospective observational study of patients with aBC treated with everolimus and ET beyond CDK4/6-i progression compiled from February 2015 to December 2022 in 4 Spanish hospitals was performed. Clinical and demographic data were collected from medical records. The main objective was to estimate the median progression-free survival (mPFS). Everolimus adverse events (AE) were registered. Quantitative variables were summarized with medians; qualitative variables with proportions and the Kaplan–Meier method were used for survival estimates. Results: One hundred sixty-one patients received everolimus plus ET (exemestane: 96, fulvestrant: 54, tamoxifen: 10, unknown: 1) after progressing on a CDK4/6 inhibitor. The median follow-up time was 15 months (interquartile range: 1–56 months). The median age at diagnosis was 49 years (range: 35–90 years). The estimated mPFS was 6.0 months (95%CI 5.3–7.8 months). PFS was longer in patients with previous CDK4/6 inhibitor therapy lasting for > 18 months (8.7 months, 95%CI 6.6–11.3 months), in patients w/o visceral metastases (8.0 months, 95%CI 5.8–10.5 months), and chemotherapy-naïve in the metastatic setting (7.2 months, 95%CI 5.9–8.4 months). Conclusion: This retrospective analysis cohort of everolimus plus ET in mBC patients previously treated with a CDK4/6 inhibitor suggests a longer estimated mPFS when compared with the mPFS with ET monotherapy obtained from current randomized clinical data. Everolimus plus ET may be considered as a valid control arm in novel clinical trial designs. [ABSTRACT FROM AUTHOR]

Endocrine therapy has become the fundamental treatment option for hormone receptor-positive (HR+) and receptor tyrosine-protein kinase erbB-2-negative (HER2-) metastatic breast cancer (mBC). While treatments incorporating cyclin-dependent kinase (CDK)4 and 6 inhibitors are more prevalent than ever, comparisons among those regimens are scarce. The aim of the present study was to identify the most effective maintenance treatment for patients with HR+ and HER2- mBC. To this end, databases including PubMed, Embase, Cochrane Library, Scopus and Google Scholar were searched from inception to August, 2023. The endpoints comprised overall survival (OS) and progression free survival (PFS). For dichotomous variants, hazard ratios (HRs) and odds ratios (ORs) were generated, while standard mean difference (SMD) was used for consecutive variants by Bayesian network meta-analysis to make pairwise comparisons among regimens, to determine the optimal therapy. These processes were conducted using Rstudio 4.2.2 orchestrated with STATA 17.0 MP. A total of 16 randomized controlled trials including 7,174 patients with 11 interventions were analyzed. Compared with aromatase inhibitor (AI), palbociclib plus AI (PalboAI) exhibited a significantly longer PFS up to the 36th month of follow-up [HR=1.7; 95% credible interval, 1.36-2.16], including on the 3rd [OR=2.22; 95% confidence interval (CI), 1.10-4.47], 6th (OR=2.39; 95% CI, 1.21-4.69), 12th (OR=1.94; 95% CI, 1.34-2.79), 18th (OR=2.38; 95% CI, 1.65-3.44), 24th (OR=2.39; 95% CI, 1.67-3.43), 30th (OR=2.10; 95% CI, 1.62-2.74) and 36th (OR=2.66; 95% CI, 1.37-5.18) month of follow-up. Additionally, abemaciclib plus fulvestrant exhibited significant effects compared with AI alone between 12 and 36 months. Ribociclib plus fulvestrant, ribociclib plus AI and dalpiciclib plus AI exerted significant effects compared with AI alone between 12 and 30 months. Considering the effect on OS and PFS together with adverse reactions, safety, medical compliance and route of administration, PalboAI was found to be the optimal treatment for HR+/HER2-mBC. However, additional head-to-head clinical trials are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: The optimal adjuvant endocrine therapy (ET) in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+) premenopausal breast cancer (BC) remains unclear. Moreover, the benefit and clinical indications of ovarian suppression (OS) is poorly elucidated. We described real‐world patterns surrounding choice of ET and clinicopathologic features which predicted treatment with OS in a contemporary cohort of premenopausal women with HR+/HER2+ BC. Methods: This retrospective analysis included premenopausal patients with nonmetastatic HR+/HER2+ BC from the CancerLinQ Discovery database from January 2010 to May 2020. Women were less than 50 years and received chemotherapy, anti‐HER2 therapy, and ET. They were categorized into 1 of 4 groups based on type of ET prescribed at initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression assessed associations between clinicopathologic features and OS use. Results: Out of 360,540 patients with BC, 937 were included. The majority (n = 818, 87%) were prescribed tamoxifen, whereas 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS and AI + OS, respectively. No clinicopathologic features predicted OS use apart from age; patients <35 years were more likely to receive OS compared with those ≥35 years (odds ratio 2.33, p < 0.001). Conclusions: This is the first real‐world study evaluating ET treatment patterns in HR+/HER2+ premenopausal BC. OS use was uncommon and the majority received tamoxifen as the preferred ET regardless of most clinicopathologic risk factors. Additional research is needed to optimize ET decisions in young women with this distinct BC subtype. [ABSTRACT FROM AUTHOR]

Purpose of Review: Pre-menopausal women diagnosed with hormone receptor (HR) breast cancer are candidates for prolonged hypoestrogenism to improve cancer outcomes. However, the disease benefit eclipses the toxicities associated with ovarian function suppression (OFS), which are often under-reported. Recent Findings: Increased risk of mortality from cardiovascular disease, bone disorders, and metabolic disorders is well reported in women with no history of cancer, after surgical oophorectomy or premature ovarian failure. Vasomotor symptoms, urogenital atrophy, weight gain, sexual dysfunction, cognitive decline, and sleep disturbances contribute to the increased non-compliance associated with OFS, especially in younger women. Summary: Balancing the toxicities of prolonged OFS with its benefits should be critically analyzed by providers when making recommendations for their patients. Supportive care to manage multi-system toxicities and to counteract the long-term impact on all-cause mortality should be emphasized by every cancer program. Future studies with OFS should incorporate patient outcomes and strategies for symptom management in addition to focusing on improving disease outcomes. [ABSTRACT FROM AUTHOR]

Background: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases. Methods: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator's choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory). Results: In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610–1.072), p = 0.1389; rPFS 0.956 (0.759–1.205), p = 0.7039; OS 0.889 (0.660–1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379–0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%. Conclusions: In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014. [ABSTRACT FROM AUTHOR]

Background Hormone receptor (HR)-positive, HER2-negative metastatic invasive lobular breast cancer (mILC) is distinct from invasive ductal cancer (IDC) in clinicopathologic and molecular characteristics, impacting its response to systemic therapy. While endocrine therapy (ET) combined with targeted therapies has shown efficacy in ET-sensitive mILC, data on chemotherapy in ET-refractory mILC remain limited. We investigated the efficacy of single-agent capecitabine (CAP) versus taxanes (TAX) in ET-refractory HR+ HER2-negative patients with mILC. Materials and Methods Using data from the MD Anderson prospectively collected breast cancer database, we identified patients with HR+ HER2-negative mILC who received prior ET and first-time chemotherapy in the metastatic setting. We compared outcomes between 173 CAP-treated and 96 TAX-treated patients. Results CAP-treated patients had significantly better median progression-free survival (PFS) than TAX-treated patients (8.8 vs 5.0 months, HR 0.63, P  < .001). Overall survival (OS) did not differ significantly between the groups (42.7 vs 36.6 months for CAP vs TAX, respectively, HR 0.84, P  = .241). Multivariate analyses for PFS and OS revealed better outcomes in subjects with fewer metastatic sites and those exposed to more lines of ET. Additionally, Black patients showed worse OS outcomes compared to White patients (HR 2.46; P  = .001). Conclusion In ET-refractory HR+ HER2-negative mILC, single-agent CAP demonstrated superior PFS compared to TAX. Our findings highlight the potential benefit of CAP in this patient subset, warranting further investigation through prospective trials. [ABSTRACT FROM AUTHOR]

Abstract Background The optimal adjuvant endocrine therapy (ET) in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+) premenopausal breast cancer (BC) remains unclear. Moreover, the benefit and clinical indications of ovarian suppression (OS) is poorly elucidated. We described real‐world patterns surrounding choice of ET and clinicopathologic features which predicted treatment with OS in a contemporary cohort of premenopausal women with HR+/HER2+ BC. Methods This retrospective analysis included premenopausal patients with nonmetastatic HR+/HER2+ BC from the CancerLinQ Discovery database from January 2010 to May 2020. Women were less than 50 years and received chemotherapy, anti‐HER2 therapy, and ET. They were categorized into 1 of 4 groups based on type of ET prescribed at initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression assessed associations between clinicopathologic features and OS use. Results Out of 360,540 patients with BC, 937 were included. The majority (n = 818, 87%) were prescribed tamoxifen, whereas 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS and AI + OS, respectively. No clinicopathologic features predicted OS use apart from age; patients

Over the past few decades, first-line therapy for treating advanced and metastatic HR+/HER2-breast cancer has transformed due to the introduction of adjuvant endocrine therapy with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i). However, there is an unmet need for novel classes of endocrine therapy with superior efficacy to improve treatment outcomes and overcome CDK4/6i resistance. New generation selective estrogen receptor degraders (SERDs), orally administered and with higher bioavailability, could potentially be the novel compounds to meet this emerging need. In this paper, we review accredited clinical studies on the combining effects of CDK4/6 inhibitors and oral SERDs, report efficacy of treatment data when available, and provide a framework for future research focusing on these promising agents.

Breast cancer currently leads among all the types of cancer in the total nmber of estimated cases worldwide, and holds fourth position in total number of deaths caused by cancer. It calls for early diagnosis and an effective treatment. Here, we explored the effect of everolimus combined with anastrozole treatment on the prognosis and serum FOXP 3 and matrix metalloproteinase 9 (MMP 9) in hormone receptor (HR) positive elderly breast cancer patients. A total of 96 elderly patients with HR positive breast cancer admitted to the hospital from April 2018 to April 2021 were selected and divided into two groups according to the random number table method. The control group (n=48) was given anastrozole, and the study group (n=48) was given everolimus and anastrozole. Recent efficacy, estrogen, adverse effects, survival rate, and test serum FOXP 3, MMP 9 levels were recorded. The results showed higher objective response rate (ORR) as (62.5%, 30/48) (41.67%, 20/48) (P <0.05), 1-year survival rate as (91.67%, 44/48) (75%, 36/48) (P <0.05), and stomatitis as (25%, 12/48) (8.33%, 4/48) (P <0.05). After treatment, estradiol (E2), luteinizing hormone (LH), FOXP 3, and MMP 9 were lower than before treatment (P <0.05), and the study group was lower than the control group (P <0.05). It has been concluded that everolimus and anastrozole therapy in HR positive elderly breast cancer can reduce estrogen and serum FOXP 3 and MMP 9 levels, with high 1-year survival rate, but with high incidence of stomatitis. [ABSTRACT FROM AUTHOR]

Purpose: This phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians’ choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC). Patients and methods: The initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL). Results: A total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7–24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0–10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1–79.0]. For patients who received ribociclib + ET, grade 3–4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3–4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died – 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related. Conclusion: The results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC. Trial registration: Anti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877.

Hormone receptor--positive (HR+) disease is the most frequently diagnosed subtype of breast cancer. Among tumor subtypes, natural course of HR+ breast cancer is indolent with favorable prognosis compared to other subtypes such as human epidermal growth factor protein 2--positive disease and triple-negative disease. HR+ tumors are dependent on steroid hormone signaling and endocrine therapy is the main treatment option. Recently, the discovery of cyclin-dependent kinase 4/6 inhibitors and their synergistic effects with endocrine therapy has dramatically improved treatment outcome of advanced HR+ breast cancer. The demonstrated efficacy of additional nonhormonal agents, such as targeted therapy against mammalian target of rapamycin and phosphatidylinositol 3-kinase signaling, poly(ADP-ribose) polymerase inhibitors, antibody-drug conjugates, and immunotherapeutic agents have further expanded the available therapeutic options. This article reviews the latest advancements in the treatment of HR+ breast cancer, and in doing so discusses not only the development of currently available treatment regimens but also emerging therapies that invite future research opportunities in the field. [ABSTRACT FROM AUTHOR]

Simple Summary: Second-line treatment strategy after the first-line CDK4/6 inhibitor with aromatase inhibitor is considered by the behavior of hormone receptor positive human epidermal growth factor receptor-2 negative (HR+HER2−) metastatic breast cancer (MBC). Progression free survival 2 was one of the association factors for overall survival of HR+HER2− MBC. Therefore, the second-line treatment strategy was important to improve prognosis in patients with HR+/HER2− MBC. Background: We analyzed real-world practice of second-line treatment in hormone receptor (HR)+ human epidermal growth factor receptor-2 (HER2)− metastatic breast cancer (MBC) following the first-line CDK4/6 inhibitor with letrozole. In addition, we evaluated the relationship between second-line treatment strategies and survival outcome. Methods: Using the clinical data warehouse, clinical information including MBC diagnosis, treatment and survival outcomes were collected. Results: In total, 305 patients were treated with the first-line palbociclib plus letrozole, and we evaluated 166 patients who were treated with second-line treatment. Of the 166 patients, 28.5% were treated with capecitabine (C), followed by exemestane with everolimus (EE) (27.3%) or cytotoxic chemotherapy other than capecitabine (T) (18.8%) and fulvestrant-based treatment or endocrine monotherapy (F) (12.7%). Eighteen patients (10.9%) were enrolled in clinical trials (CT). With regard to treatment strategies, and the median progression-free survival of second-line treatment in a metastatic setting (PFS2) was 7.4 months with C, 5.2 months with EE, 4.8 months with T, 3.6 months with F, and 3.6 months with CT (p = 0.066). In patients with visceral organ disease progression, C (31.3%) or T(31.3%) was the most common second-line treatment followed by EE (21.9%). Most of the 47 patients with bone metastasis alone were treated with EE (38.2%), followed by C (23.4%) and F (21.3%) (p = 0.008). The median overall survival of second-line treatment in a metastatic setting (OS2) was 42.3 months with C, 35.7 months with F, 30.7 months with EE, and 23.1 months with T. The median OS2 for those in CT was not reached (p = 0.064). ER driven BC, disease progression site and PFS2 were associated with OS and OS2 in HR+HER2− MBC (ps < 0.05). Conclusions: We suggested the second line treatment strategy was important to improve prognosis in patients with HR+/HER2− MBC, especially given the recent standardization of first-line treatment and the many available second-line options. [ABSTRACT FROM AUTHOR]

Metastatic hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer survival outcomes have improved significantly; however, once endocrine resistance develops, response rates to systemic treatments are limited. Within the developing field of antibody-drug conjugates, the TROPiCS-02 study showed a significant improvement in progression-free survival with sacituzumab govitecan compared with physician's choice of chemotherapy in patients with endocrine-resistant, metastatic, HR+/HER2-breast cancer. Additionally, overall survival similarly improved (14.4 months versus 11.2 months, respectively). We discuss the role of sacituzumab govitecan and its role in practice, looking at the direct impact it has in metastatic HR+/HER2-breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: We have previously shown that the glucocorticoid receptor (GCR) protein was reduced in invasive breast carcinoma compared to normal breast tissue. Here, we evaluated the level of serum/glucocorticoid-regulated kinase 1 (SGK1) and B-cell lymphoma 2 (Bcl-2) levels in the corresponding primary breast cancer tissue. SGK1 was higher and Bcl-2 was lower in breast cancer tissue compared to normal breast tissue. Similar to previous reports, we found that the expression of the Bcl-2 protein was associated with longer survival. We observed a correlation between the expression of the GCR and the Bcl-2 protein. The expression of the Bcl-2 protein was higher among cases who self-reported their race and ethnicity as non-Hispanic Black people. It is crucial to understand molecular alterations in breast cancer and how they relate to clinicopathologic factors. We have previously shown that the glucocorticoid receptor (GCR) protein expression was reduced in invasive breast carcinoma compared to normal breast tissue. Glucocorticoids, signaling through the GCR, regulate several cellular processes via downstream targets such as serum/glucocorticoid-regulated kinase 1 (SGK1) and B-cell lymphoma 2 (Bcl-2). We measured the expression of SGK1 and Bcl-2, in respective breast cancer tissue arrays, from a multiracial cohort of breast cancer patients. Higher cytoplasmic SGK1 staining was stronger in breast cancer tissue compared to normal tissue, especially in hormone receptor-negative cases. Conversely, the expression of cytoplasmic Bcl-2 was reduced in breast cancer compared to normal tissue, especially in hormone receptor-negative cases. Bcl-2 staining was associated with the self-reported racial/ethnic category, an earlier clinical stage, a lower histological grade, and a higher survival rate. Bcl-2 expression was associated with longer survival in models adjusted for age and race (HR = 0.32, 95% CI: 0.15, 0.65), and Bcl-2 expression remained strongly positively associated with protection from breast cancer death, with additional adjustments for ER/PR status (HR = 0.41, 95% CI: 0.2, 0.85). SGK1 and Bcl-2 may play biological roles in breast cancer development and/or progression. [ABSTRACT FROM AUTHOR]

Very young premenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+HER2−) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained. Genomic sequencing was applied to HR+HER2− tumours from patients enrolled in the Suppression of Ovarian Function Trial (SOFT) to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, n = 1258; whole-exome sequencing in a young-age, case-control subsample, n = 82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI) and overall survival (OS). Younger women (<40 years, n = 359) compared with older women (≥40 years, n = 917) had significantly higher frequencies of mutations in GATA3 (19% versus 16%) and CN amplifications (CNAs) (47% versus 26%), but significantly lower frequencies of mutations in PIK3CA (32% versus 47%), CDH1 (3% versus 9%), and MAP3K1 (7% versus 12%). Additionally, they had significantly higher frequencies of features suggestive of HRD (27% versus 21%) and a higher proportion of PIK3CA mutations with concurrent CNAs (23% versus 11%). Genomic features suggestive of HRD, PIK3CA mutations with CNAs, and CNAs were associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% aged ≥40 years. Poor prognostic features [ n = 584 (46%)] versus none [ n = 692 (54%)] had an 8-year DRFI of 84% versus 94% and OS of 88% versus 96%. Younger women (<40 years) had the poorest outcomes: 8-year DRFI 74% versus 85% and OS 80% versus 93%, respectively. These results provide insights into genomic alterations that are enriched in young women with HR+HER2− EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials. • Young women aged <40 years with HR+HER2− EBC have a higher risk of recurrence and death than older women. • Genomic features of HRD, PIK3CA mutations with CNAs, and CNAs are enriched in young women. • Targeted therapies to these enriched genomic features should be considered for incorporation in future clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: CDK4/6 inhibitors (CDK4/6i) with endocrine therapy are the established first-line treatment for metastatic and advanced hormone receptor-positive breast cancer (mBC). Recently, there has been an expansion in available next lines of therapy; however, optimal sequencing remains unclear. This paper reviews data on the efficacy and response rates of approved therapeutic options, and when possible, discusses their efficacy in the setting of prior exposure to CDK4/6i. This paper also seeks to review emerging targets and therapeutics that may be approved in the future for this patient population. Front-line therapy for advanced and metastatic hormone receptor positive (HR+), HER2 negative (HER−) advanced or metastatic breast cancer (mBC) is endocrine therapy with a CDK4/6 inhibitor (CDK4/6i). The introduction of CDK4/6i has dramatically improved progression-free survival and, in some cases, overall survival. The optimal sequencing of post-front-line therapy must be personalized to patients' overall health and tumor biology. This paper reviews approved next lines of therapy for mBC and available data on efficacy post-progression on CDK4/6i. Given the success of endocrine front-line therapy, there has been an expansion in therapies under clinical investigation targeting the estrogen receptor in novel ways. There are also clinical trials ongoing attempting to overcome CDK4/6i resistance. This paper will review these drugs under investigation, review efficacy data when possible, and provide descriptions of the adverse events reported. [ABSTRACT FROM AUTHOR]

Background: Approximately 75% of breast cancer (BC) is associated with luminal differentiation expressing endocrine receptors (ER). For ER+ HER2− tumors, adjuvant endocrine therapy (ET) is the cornerstone treatment. Although relapse events steadily continue, the ET benefits translate to dramatically lengthen life expectancy with bearable side-effects. This review of ER+ HER2− female BC outlines suitable adjuvant treatment strategies to help guide clinical decision making around appropriate therapy. Methods: A literature search was conducted in Embase, Medline, and the Cochrane Libraries, using ER+ HER−, ET BC keywords. Results: In low-risk patients: five years of ET is the standard option. While Tamoxifen remains the preferred selection for premenopausal women, AI is the choice for postmenopausal patients. In the high-risk category: ET plus/minus OFS with two years of Abemaciclib is recommended. Although extended ET for a total of ten years is an alternative, the optimal AI duration is undetermined; nevertheless an additional two to three years beyond the initial five years may be sufficient. In this postmenopausal group, bisphosphonate is endorsed. Conclusions: Classifying the risk category assists in deciding the treatment route and its optimal duration. Tailoring the breadth of ET hinges on a wide array of factors to be appraised for each individualized case, including weighing its benefits and harms.

Mucinous carcinoma of the breast is a type of well-differentiated adenocarcinoma, a rare subtype of infiltrating ductal carcinoma. It represents approximately 2% of all invasive breast carcinomas. The mean age of presentation is 65 years, with an incidence of 1% in women younger than 35 years. Depending on the mucin content of the carcinoma, they are described as pure or mixed; the distinction between the 2 is important for prognosis and treatment. The treatment of special types of breast cancer is still controversial due to the limited amount of evidence, however, the main treatment for breast cancer is still surgery. We present a case of a 29-year-old patient with mucinous carcinoma of the breast with a delay in its management, but with a favorable postoperative result.

Background: More than half of Chinese patients with hormone receptor positive (HR+) ductal carcinoma in situ (DCIS) are treated with mastectomy, and usually subjected to postoperative endocrine therapy (ET). Given that long-term ET can cause severe adverse effects it is important to determine the beneficial effect and safety of post-mastectomy ET on the disease-free survival (DFS) and adverse events in patients with HR+ DCIS. Methods: To explore beneficial effect and safety of post-mastectomy ET in patients with HR+ DCIS, we performed a multicenter, population-based study. This retrospective study analyzed the DFS and adverse events in 1037 HR+ DCIS Chinese patients with or without post-mastectomy ET from eight breast centers between 2006 and 2016. The median follow-up time period was 86 months. Results: There were 791 DCIS patients receiving ET (ET group). Those patients were followed up for a median of 86 months (range, 60–177 months). There were 23 cases with tumor recurrence or distant metastasis. There were similar 5-year DFS rates and DFS between the ET and non-ET groups, even for those with high-risk factors. Conversely, 37.04% of patients suffered from adverse events after ET, which were significantly higher than those in the non-ET group. Conclusions: ET after mastectomy did not benefit patients with HR+ DCIS for their DFS, rather increased adverse events in those patients. Therefore, ET after mastectomy may not be recommended for patients with HR+ DCIS, even for those with high-risk factors, such as multifocal, microinvasive, and higher T stage. Funding: This study was supported by grants from Outstanding Scientific Fund of Shengjing Hospital (201803) and Outstanding Young Scholars of Liaoning Province (2019-YQ-10).

Cyclin-dependent kinases 4/6 ( CDK4/6 ) inhibitors are anti-tumor agents for the treatment of hormone receptor-positive breast cancer. Palbociclib, abemaciclib and dalpiciclib have been approved for the treatment of breast cancer in China. Common adverse effects of CDK4/6 inhibitors include bone marrow suppression, gastrointestinal toxicities, liver dysfunction, and skin or subcutaneous tissue adverse reactions (AEs). The Breast Cancer Expert Group of Chinese Society of Clinical Oncology (CSCO) summarized the incidence, clinical manifestations, and grading of the AEs. This expert consensus reports measures of AE management on the basis of experience of clinical practice and the latest advances worldwide, aiming to guide clinical practice by the way of managing AE and help to choose the best treatment regimen. [ABSTRACT FROM AUTHOR]

Background: To observe whether guideline non-adherence in initial palliative treatment choices for premenopausal hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (MBC) patients result in worse clinical outcomes in the Chinese population. Methods: The China National Cancer Center database was used to identify 2194 patients diagnosed between 2004 and 2015. A total of 451 premenopausal patients with HR + HER2- MBC were included. Clinicopathological features and survival information were extracted. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared using log-rank test. Results: The number of patients receiving initial chemotherapy, endocrine therapy and chemo-endocrine therapy were 222 (49.2%), 80 (17.7%), and 149 (33.0%), respectively. Patients receiving initial chemotherapy were more likely to be luminal B subtype, had more de novo stage IV disease and more liver metastasis, compared with patients receiving initial endocrine therapy. Both PFS and OS were significantly longer for chemo-endocrine therapy group (median PFS 18.9 months and OS 75.0 months), than for endocrine therapy group (median PFS 11.7 months and OS 53.5 months), and chemotherapy group (median PFS 7.1 months and OS 43.9 months). In multivariate analysis, none of the three treatment strategies were independently associated with PFS or OS. Conclusion: In real world, a high percentage of premenopausal patients with HR + HER2- disease received chemotherapy as initial palliative treatment in China, which was not associated with worsened survival. Further studies with larger sample size across China are needed to explore the relationship between this guideline non-adherence and clinical outcomes.

Age is a risk factor for breast cancer in females, and over 60% of female breast cancer deaths occur in those aged 65 and older. As the population in the United States continues to age, it is expected that there will be a commensurate increase in the number of women diagnosed with breast cancer, making understanding of effective treatment and management of breast cancer in the elderly essential.Here, we review the treatment and management of early breast cancer in the elderly. We report a case of invasive mucinous carcinoma in an 80-year-old female detected on routine clinical breast exam by her primary care physician. Mucinous carcinoma of the breast is a type of rare invasive neoplasm that generally carries an excellent prognosis. Following an ultrasound-guided core needle biopsy, a right breast needle localized segmental mastectomy was performed and the patient was prescribed an aromatase inhibitor for hormone-receptor positive tumor. After a follow-up of 8 years, the patient remains free of recurrence or metastasis and vibrantly living meaningful daily life.

Breast cancer (BC) is the most prevalent malignancy in women, and most of their deaths from BC are caused by metastases. The bone, liver, lungs, and skin are the most frequently involved organs in metastases. We report a rare case of middle ear metastasis from BC in a 67-year-old woman. The patient had a curative modified radical mastectomy for her right BC 24 years ago and was treated with letrozole as a first-line therapy for the recurrent disease since 2016. After more than 5.5 years of treatment, computed tomography revealed otitis media with mastoiditis, and a granular tumor was found in the attic space and mesotympanum during the operation with the initial symptom of decreased left ear hearing. The mass was incompletely removed, and a biopsy eventually confirmed metastatic BC. There are very few case reports in the literature. Our case highlights the importance of surgical biopsy in differentiating middle ear neoplastic lesions. [ABSTRACT FROM AUTHOR]

Simple Summary: Aromatase inhibitors (AIs) remain key elements of endocrine therapy for patients with hormone receptor positive HER2 negative metastatic breast cancer (HR+ HER2− MBC). Recent advances include the use of CDK 4/6 inhibitors or PIK3CA inhibitor in the clinic; however, few immunotherapy trials have been conducted in HR+ HER2− metastatic disease. The current phase II trial was designed to test the safety and efficacy of AIs in combination with immune checkpoint inhibitor pembrolizumab in patients with HR+ HER2− MBC (NCT 02648477). This combination was well tolerated, but minimal clinical activity was observed likely due to lack of PD-L1 pre-selection and heavily pretreated patient population. This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) in a phase II study with a safety lead-in (NCT 02648477). Patients received pembrolizumab plus AI up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria were HR+ HER2− MBC; RECIST v1.1 measurable disease; adequate organ function; and ECOG 0-1. Primary endpoints were safety and overall response rate. A 3-at-risk design was used for the safety lead-in with a targeted accrual of 20 patients. Grade 2 adverse events (AEs) included 35% fatigue, 20% rash, and 10% hot flashes. Grade 3 immune-related AEs (irAEs) related to pembrolizumab included 5% elevated AST/ALT, 5% rash, and 5% lymphopenia. Two (10%) patients had partial responses, three (15%) had stable disease, and 15 (75%) had progression of disease. Median progression-free survival was 1.8 months (95% CI 1.6, 2.6), median overall survival was 17.2 months (95% CI 9.4, NA), and median follow-up time was 40.1 months (range 31.3–46.8 months). The combination was well tolerated, but clinical activity was comparable to AI alone. [ABSTRACT FROM AUTHOR]

Endocrine therapy has become the fundamental treatment option for hormone receptor-positive (HR + ) and receptor tyrosine-protein kinase erbB-2-negative (HER2 - ) metastatic breast cancer (mBC). While treatments incorporating cyclin-dependent kinase (CDK)4 and 6 inhibitors are more prevalent than ever, comparisons among those regimens are scarce. The aim of the present study was to identify the most effective maintenance treatment for patients with HR + and HER2 - mBC. To this end, databases including PubMed, Embase, Cochrane Library, Scopus and Google Scholar were searched from inception to August, 2023. The endpoints comprised overall survival (OS) and progression free survival (PFS). For dichotomous variants, hazard ratios (HRs) and odds ratios (ORs) were generated, while standard mean difference (SMD) was used for consecutive variants by Bayesian network meta-analysis to make pairwise comparisons among regimens, to determine the optimal therapy. These processes were conducted using Rstudio 4.2.2 orchestrated with STATA 17.0 MP. A total of 16 randomized controlled trials including 7,174 patients with 11 interventions were analyzed. Compared with aromatase inhibitor (AI), palbociclib plus AI (PalboAI) exhibited a significantly longer PFS up to the 36th month of follow-up [HR=1.7; 95% credible interval, 1.36-2.16], including on the 3rd [OR=2.22; 95% confidence interval (CI), 1.10-4.47], 6th (OR=2.39; 95% CI, 1.21-4.69), 12th (OR=1.94; 95% CI, 1.34-2.79), 18th (OR=2.38; 95% CI, 1.65-3.44), 24th (OR=2.39; 95% CI, 1.67-3.43), 30th (OR=2.10; 95% CI, 1.62-2.74) and 36th (OR=2.66; 95% CI, 1.37-5.18) month of follow-up. Additionally, abemaciclib plus fulvestrant exhibited significant effects compared with AI alone between 12 and 36 months. Ribociclib plus fulvestrant, ribociclib plus AI and dalpiciclib plus AI exerted significant effects compared with AI alone between 12 and 30 months. Considering the effect on OS and PFS together with adverse reactions, safety, medical compliance and route of administration, PalboAI was found to be the optimal treatment for HR + /HER2 - mBC. However, additional head-to-head clinical trials are warranted to confirm these findings., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Jiang et al.)

Purpose: To identify prognostic factors of invasive–disease free survival (iDFS) in women with non-metastatic hormone receptor positive (HR+) breast cancer (BC) in daily routine practice. Methods: We performed a retrospective study using data from the Côte d’Or breast and gynecological cancer registry in France. All women diagnosed with primary invasive non-metastatic HR + BC from 1998 to 2015 and treated by endocrine therapy (ET) were included. Women with bilateral tumors or who received ET for either metastasis or relapse were excluded. We performed adjusted survival analysis and Cox regression to identify prognostic factors of iDFS. Results: A total of 3976 women were included. Age at diagnosis, ET class, SBR grade, treatment, stage and comorbidity were independently associated with iDFS. Women who had neither surgery nor radiotherapy had the highest risk of recurrence (HR = 3.75, 95%CI [2.65–5.32], p

Background: We analyzed real-world practice of second-line treatment in hormone receptor (HR)+ human epidermal growth factor receptor-2 (HER2)− metastatic breast cancer (MBC) following the first-line CDK4/6 inhibitor with letrozole. In addition, we evaluated the relationship between second-line treatment strategies and survival outcome. Methods: Using the clinical data warehouse, clinical information including MBC diagnosis, treatment and survival outcomes were collected. Results: In total, 305 patients were treated with the first-line palbociclib plus letrozole, and we evaluated 166 patients who were treated with second-line treatment. Of the 166 patients, 28.5% were treated with capecitabine (C), followed by exemestane with everolimus (EE) (27.3%) or cytotoxic chemotherapy other than capecitabine (T) (18.8%) and fulvestrant-based treatment or endocrine monotherapy (F) (12.7%). Eighteen patients (10.9%) were enrolled in clinical trials (CT). With regard to treatment strategies, and the median progression-free survival of second-line treatment in a metastatic setting (PFS2) was 7.4 months with C, 5.2 months with EE, 4.8 months with T, 3.6 months with F, and 3.6 months with CT (p = 0.066). In patients with visceral organ disease progression, C (31.3%) or T(31.3%) was the most common second-line treatment followed by EE (21.9%). Most of the 47 patients with bone metastasis alone were treated with EE (38.2%), followed by C (23.4%) and F (21.3%) (p = 0.008). The median overall survival of second-line treatment in a metastatic setting (OS2) was 42.3 months with C, 35.7 months with F, 30.7 months with EE, and 23.1 months with T. The median OS2 for those in CT was not reached (p = 0.064). ER driven BC, disease progression site and PFS2 were associated with OS and OS2 in HR+HER2− MBC (ps < 0.05). Conclusions: We suggested the second line treatment strategy was important to improve prognosis in patients with HR+/HER2− MBC, especially given the recent standardization of first-line treatment and the many available second-line options.

Background: Approximately 75% of breast cancer (BC) is associated with luminal differentiation expressing endocrine receptors (ER). For ER+ HER2− tumors, adjuvant endocrine therapy (ET) is the cornerstone treatment. Although relapse events steadily continue, the ET benefits translate to dramatically lengthen life expectancy with bearable side-effects. This review of ER+ HER2− female BC outlines suitable adjuvant treatment strategies to help guide clinical decision making around appropriate therapy. Methods: A literature search was conducted in Embase, Medline, and the Cochrane Libraries, using ER+ HER−, ET BC keywords. Results: In low-risk patients: five years of ET is the standard option. While Tamoxifen remains the preferred selection for premenopausal women, AI is the choice for postmenopausal patients. In the high-risk category: ET plus/minus OFS with two years of Abemaciclib is recommended. Although extended ET for a total of ten years is an alternative, the optimal AI duration is undetermined; nevertheless an additional two to three years beyond the initial five years may be sufficient. In this postmenopausal group, bisphosphonate is endorsed. Conclusions: Classifying the risk category assists in deciding the treatment route and its optimal duration. Tailoring the breadth of ET hinges on a wide array of factors to be appraised for each individualized case, including weighing its benefits and harms. [ABSTRACT FROM AUTHOR]

Yang Li,1 Yuhan Zhang,1 Shuaibing Wang,2 Su Lu,1 Yixuan Song,1 Hong Liu1 1The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China; 2Oncology Department, China National Petroleum Corporation Central Hospital, Langfang, Hebei Province, 065000, People’s Republic of ChinaCorrespondence: Hong LiuThe Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Huanhu West Road, Hexi District, Tianjin, 300060, People’s Republic of ChinaTel +86-18622221169Email liuhongzhang0101@163.comPurpose: We aimed to examine the effect of pregnancy on prognosis in young breast cancer (YBC) patients with hormone receptor (HR) positive after surgery and the safety of interrupting endocrine therapy (ET).Methods: A retrospective cohort study was performed in patients who became pregnant after BC surgery under the age of 35 and were matched (1:4) to nonpregnant patients from 2006 to 2014. The primary endpoints were disease-free survival (DFS) and overall survival (OS) in HR-positive BC patients, and the secondary endpoints were DFS and OS in HR-negative BC patients and the whole population. Subgroup analyses included the DFS of patients who became pregnant within 5 years after surgery and DFS according to the ET interval time (≤ 30 months v > 30 months) in the pregnant group.Results: A total of 1323 YBC patients were collected in our study, which included 68 pregnant patients and 264 matched nonpregnant patients. There were no statistically significant differences in DFS and OS among HR-positive patients (P=0.657, P=0.250, respectively) and the whole population (P=0.058, P=0.152, respectively). A BC pregnancy interval ≤ 5 years showed a better DFS (P=0.042), and an ET interval ≤ 30 months had a worse DFS (P = 0.01).Conclusion: This study did not observe a worse prognosis in patients with HR-positive disease who became pregnant after BC surgery, and an ET interval less than 30 months in pregnant patients led to a worse outcome. Patients were able to become pregnant within 5 years after surgery.Keywords: young breast cancer, prognosis, pregnancy, hormone receptor positive, endocrine therapy

Over the past few decades, first-line therapy for treating advanced and metastatic HR+/HER2-breast cancer has transformed due to the introduction of adjuvant endocrine therapy with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i). However, there is an unmet need for novel classes of endocrine therapy with superior efficacy to improve treatment outcomes and overcome CDK4/6i resistance. New generation selective estrogen receptor degraders (SERDs), orally administered and with higher bioavailability, could potentially be the novel compounds to meet this emerging need. In this paper, we review accredited clinical studies on the combining effects of CDK4/6 inhibitors and oral SERDs, report efficacy of treatment data when available, and provide a framework for future research focusing on these promising agents. • Oral SERDs have come forward as a promising alternative to fulvestrant. • Elacestrant and camizestrant improved PFS in ER+/HER2-advanced or metastatic breast cancer, especially with ESR1 mutations. • Elacestrant is the first approved oral SERD, after showing efficacy and good tolerability especially in ESR1 mutated tumors. • Oral SERDs exhibit potential to be established as new combination agents along with CDK4/6 inhibitors. [ABSTRACT FROM AUTHOR]

Front-line therapy for advanced and metastatic hormone receptor positive (HR+), HER2 negative (HER−) advanced or metastatic breast cancer (mBC) is endocrine therapy with a CDK4/6 inhibitor (CDK4/6i). The introduction of CDK4/6i has dramatically improved progression-free survival and, in some cases, overall survival. The optimal sequencing of post-front-line therapy must be personalized to patients’ overall health and tumor biology. This paper reviews approved next lines of therapy for mBC and available data on efficacy post-progression on CDK4/6i. Given the success of endocrine front-line therapy, there has been an expansion in therapies under clinical investigation targeting the estrogen receptor in novel ways. There are also clinical trials ongoing attempting to overcome CDK4/6i resistance. This paper will review these drugs under investigation, review efficacy data when possible, and provide descriptions of the adverse events reported.

Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21–95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0–1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0–5) prior lines of endocrine therapy and median 0 (range 0–6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1–88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0–88). This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients. • Fulvestrant is licensed for the treatment of hormone receptor-positive advanced breast cancer in postmenopausal women. • One of the largest studied patient cohorts treated with fulvestrant, with data collection from nine UK centres. • Results confirm a modest radiological response rate even in a predominantly pretreated cohort. • Fair access to fulvestrant monotherapy in England should be standard to enable its use in patients most likely to benefit. [ABSTRACT FROM AUTHOR]

To observe whether guideline non-adherence in initial palliative treatment choices for premenopausal hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (MBC) patients result in worse clinical outcomes in the Chinese population. The China National Cancer Center database was used to identify 2194 patients diagnosed between 2004 and 2015. A total of 451 premenopausal patients with HR + HER2- MBC were included. Clinicopathological features and survival information were extracted. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared using log-rank test. The number of patients receiving initial chemotherapy, endocrine therapy and chemo-endocrine therapy were 222 (49.2%), 80 (17.7%), and 149 (33.0%), respectively. Patients receiving initial chemotherapy were more likely to be luminal B subtype, had more de novo stage IV disease and more liver metastasis, compared with patients receiving initial endocrine therapy. Both PFS and OS were significantly longer for chemo-endocrine therapy group (median PFS 18.9 months and OS 75.0 months), than for endocrine therapy group (median PFS 11.7 months and OS 53.5 months), and chemotherapy group (median PFS 7.1 months and OS 43.9 months). In multivariate analysis, none of the three treatment strategies were independently associated with PFS or OS. In real world, a high percentage of premenopausal patients with HR + HER2- disease received chemotherapy as initial palliative treatment in China, which was not associated with worsened survival. Further studies with larger sample size across China are needed to explore the relationship between this guideline non-adherence and clinical outcomes. • Large retrospective analysis focusing on premenopausal patients with HR + HER2-metastatic breast cancer in China. • A high percentage of the study patients received chemotherapy as initial palliative treatment. • No differences in survival were observed on first-line chemotherapy or endocrine therapy. • Further studies across China are needed to explore the relationship between guideline non-adherence and clinical outcomes. [ABSTRACT FROM AUTHOR]

Purpose: PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib–paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC). Methods: Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1–21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). Results: Overall, 146 patients were randomized to ipatasertib–paclitaxel and 76 to placebo–paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71–1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib–paclitaxel vs 1% with placebo–paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%). Conclusion: Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib–paclitaxel safety profile was consistent with each agent's known adverse effects. Trial registration NCT03337724. [ABSTRACT FROM AUTHOR]

Jiangping Yang,1,* Jiaqi Han,1,* Maolang Tian,1 Kun Tian,2 Wenjun Liao,1 Xi Yan3,4 1Department of Head and Neck Oncology and Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China; 2Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 3Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China; 4Laboratory of Molecular Diagnosis of Cancer, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xi YanDepartment of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of ChinaTel +86 189 8060 1777Email yanxi@scu.edu.cnPurpose: Ribociclib has provided significant improvements in progression-free survival (PFS) and overall survival (OS) of postmenopausal patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). However, given the high cost of ribociclib, its value must be evaluated based on cost-effectiveness. Thus, we aimed to explore the cost-effectiveness of ribociclib for postmenopausal patients with HR-positive and HER2-negative ABC.Methods: A comprehensive Markov model was developed to estimate the cost-effectiveness of ribociclib plus fulvestrant versus placebo plus fulvestrant as first-line treatment for HR-positive, HER2-negative ABC. Variables were estimated based on data from the randomized Phase III MONALEESA-3 trial. Ten-year values were estimated for quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Direct treatment costs were estimated from the perspective of a United States payer. One-way and probabilistic sensitivity analyses were conducted to confirm the model’s robustness.Results: Ribociclib plus fulvestrant increased the treatment cost by $382,172 and provided 0.47 QALYs, relative to fulvestrant alone, which corresponded to an ICER of $813,132 per QALY. Sensitivity analyses revealed that ribociclib was unlikely to be cost-effective even under the most favorable assumptions. When the cost of ribociclib was 50% chance of cost-effectiveness at a willingness-to-pay threshold of $150,000/QALY. Subgroup analyses also confirmed that ribociclib was not cost-effective.Conclusion: At current drug prices in the United States, ribociclib is unlikely to be cost-effective for treating postmenopausal patients with HR-positive HER2-negative ABC. Despite the clinical benefits of ribociclib, its cost would need to decrease to provide more favorable economic outcomes.Keywords: cost-effectiveness, ribociclib, fulvestrant, breast cancer, hormone receptor positive

Metastatic breast cancer is considered incurable. Data regarding how patients with oligometastatic breast cancer might best be treated is limited, with questions concerning the role of locoregional treatment, inclusive of surgery and radiotherapy, and local treatment to the metastatic site. Here we present a case of a 42-year-old woman with oligometastatic HR+/HER2- breast cancer, who achieved a complete radiological response for the metastatic site, after receiving ribociclib and undergoing breast surgery. We review the current evidence for locoregional treatment, and discuss the role of cyclin inhibitors in systemic treatment.

Reproductive and hormonal factors may influence breast cancer risk via endogenous estrogen exposure. Cumulative menstrual months (CMM) can be used as a surrogate measure of this exposure. Using harmonized data from four population‐based breast cancer studies (7284 cases and 7242 controls), we examined ethnicity‐specific associations between CMM and breast cancer risk using logistic regression, adjusting for menopausal status and other risk factors. Higher CMM was associated with increased breast cancer risk in non‐Hispanic Whites, Hispanics and Asian Americans regardless of menopausal status (all FDR adjusted P trends =.0004), but not in African Americans. In premenopausal African Americans, there was a suggestive trend of lower risk with higher CMM. Stratification by body mass index (BMI) among premenopausal African American women showed a nonsignificant positive association with CMM in nonobese (BMI <30 kg/m2) women and a significant inverse association in obese women (OR per 50 CMM = 0.56, 95% CI 0.37‐0.87, Ptrend =.03). Risk patterns were similar for hormone receptor positive (HR+; ER+ or PR+) breast cancer; a positive association was found in all premenopausal and postmenopausal ethnic groups except in African Americans. HR− (ER− and PR−) breast cancer was not associated with CMM in all groups combined, except for a suggestive positive association among premenopausal Asian Americans (OR per 50 CMM = 1.33, P =.07). In summary, these results add to the accumulating evidence that established reproductive and hormonal factors impact breast cancer risk differently in African American women compared to other ethnic groups, and also differently for HR− breast cancer than HR+ breast cancer. What's new? Evidence suggests that breast cancer risk is influenced by endogenous estrogen exposure, a surrogate measure of which may be cumulative menstrual months (CMM). Here, associations between breast cancer risk and CMM were investigated for four major ethnic groups in the United States. Analyses reveal positive links between CMM and breast cancer risk in premenopausal and postmenopausal Asian Americans, Hispanics, and non‐Hispanic whites. An inverse association was detected among obese premenopausal African American women. The observed differences in risk in relation to CMM highlight the importance of ongoing investigations of breast cancer risk for diverse ethnic groups and breast cancer subtypes. [ABSTRACT FROM AUTHOR]

Background: Most breast cancers (BCs) in men are hormone receptor–positive. Adjuvant tamoxifen is part of the standard treatment of these patients. Small, single‐institution studies have suggested that men have high rates of discontinuing adjuvant endocrine treatment. The authors examined rates of tamoxifen discontinuation and medication adherence in a large population‐based cohort of male patients with BC. Methods: In the Surveillance, Epidemiology, and End Results–Medicare database, male patients with invasive nonmetastatic BC, diagnosed between 2007 and 2013, who were ≥65 years old, had Part D coverage, and had tamoxifen prescriptions within 1 year of diagnosis were identified. Adherence was defined as a medication possession ratio of ≥80% among those patients who were filling tamoxifen prescriptions. Logistic regression model was used to assess predictors of tamoxifen adherence. Results: A total of 451 patients met eligibility criteria. The median age at diagnosis was 75 years. The median follow‐up was 32.5 months. The rates of tamoxifen discontinuation were 15.8%, 24.3%, 31.3%, 36.9%, and 48.3% at 1, 2, 3, 4, and 5 years after diagnosis, respectively. Among the men who were still taking tamoxifen, the corresponding adherence rates were 76.9%, 73.6%, 68.7%, 64.8%, and 60.2%. In the adjusted model, significant predictors of lower adherence included residing in a high poverty area (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.28‐2.12) and a Charlson comorbidity score of ≥2 (OR, 0.46; 95% CI, 0.22‐0.97). Conclusion: Older men with breast cancer have high rates of tamoxifen discontinuation, with 48% of all patients discontinuing tamoxifen before the end of year 5. Additionally, even among those patients continuing tamoxifen, a substantial number of patients are nonadherent. Further research should evaluate potentially modifiable reasons for treatment discontinuation and lack of adherence to tamoxifen. On the basis of an analysis, older men with breast cancer have high rates of tamoxifen discontinuation, with 48% of all patients discontinuing tamoxifen before the end of year 5. In addition, even among those patients continuing tamoxifen, a substantial number of patients are nonadherent. [ABSTRACT FROM AUTHOR]

Estrogen receptor (ER) is the major driver of most metastatic breast cancers (mBCs). Endocrine therapy (ET) is the most effective treatment for ER + mBC, but its effectiveness is limited by high rates of de novo and acquired resistance. A growing understanding of the biological characteristics and complexity of the ER pathway and the mechanisms of ET resistance has led to the development of a new generation of targeted therapies. One such mechanism is the cell cycle signaling pathways, which lead to the development of cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) that have, in turn, transformed the management of such tumors. Another important mechanism is the alteration of the phosphatidylinositol 3′-kinase/AKT/mammalian target of rapamycin pathway. Drugs targeting each component of these pathways are currently used in clinical practice, and several more are in development. As a result, a myriad of new targeted therapies are consistently being added to the clinical oncologist armamentarium. Navigating the evolving and highly complex treatment landscape of HR + /HER2− mBC remains both an art and a challenge. In this review, we discuss the biological features of HR + /HER2− mBC and the different mechanisms of resistance to ET. We also discuss the management of mBC as the disease changes from endocrine-sensitive to endocrine-resistant. [ABSTRACT FROM AUTHOR]

Background: The 21-gene assay recurrence score (RS) provides additional information on recurrence risk of breast cancer patients and prediction of chemotherapy benefit. Previous studies that examined the contribution of the individual genes and gene modules of RS were conducted mostly in postmenopausal patients. We aimed to evaluate the gene modules of RS in patients of different ages. Methods: A total of 1,078 estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients diagnosed between January 2009 and March 2017 from Shanghai Jiao Tong University Breast Cancer Data Base were included. All patients were divided into three subgroups: Group A, ≤40 years and premenopausal (n = 97); Group B, >40 years and premenopausal (n = 284); Group C, postmenopausal (n = 697). The estrogen, proliferation, invasion, and HER2 module scores from RS were used to characterize the respective molecular features. Spearman correlation and analysis of the variance tests were conducted for RS and its constituent modules. Results: In patients >40 years, RS had a strong negative correlation with its estrogen module (ρ = −0.76 and −0.79 in Groups B and C) and a weak positive correlation with its invasion module (ρ = 0.29 and 0.25 in Groups B and C). The proliferation module mostly contributed to the variance in young patients (37.3%) while the ER module contributed most in old patients (54.1% and 53.4% in Groups B and C). In the genetic high-risk (RS >25) group, the proliferation module was the leading driver in all patients (ρ = 0.38, 0.53, and 0.52 in Groups A, B, and C) while the estrogen module had a weaker correlation with RS. The impact of ER module on RS was stronger in clinical low-risk patients while the effect of the proliferation module was stronger in clinical high-risk patients. The association between the RS and estrogen module was weaker among younger patients, especially in genetic low-risk patients. Conclusions: RS was primarily driven by the estrogen module regardless of age, but the proliferation module had a stronger impact on RS in younger patients. The impact of modules varied in patients with different genetic and clinical risks. [ABSTRACT FROM AUTHOR]