Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2–), PIK3CA-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. Early detection of hyperglycemia and timely intervention have a key role in achieving optimal glycemic control and maintaining alpelisib dose intensity to optimize the benefit of this drug. A glycemic support program implemented by an endocrinology–oncology collaborative team may be very useful in this regard. Lifestyle modifications, mainly comprising a reduced-carbohydrate diet, and a designated stepwise, personalized antihyperglycemic regimen, based on metformin, sodium–glucose co-transporter 2 inhibitors, and pioglitazone, are the main tools required to address the insulin-resistant hyperglycemia induced by alpelisib. In this report, based on the consensus of 14 oncologists and seven endocrinologists, we provide guidance for hyperglycemia management strategies before, during, and after alpelisib therapy for HR+, HER2–, PIK3CA-mutated breast cancer, with a focus on a proactive, multidisciplinary approach.

Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy. POSITIVE enrolled women with stage I-III HR + early breast cancer, ≤42 years, who had received 18-30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration. From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were <35 years at enrolment (42.7 %), had mastectomy (59.0 %) and received tamoxifen alone (59.8 %). More Asian women were nulliparous (81.0 %), had node-negative disease (76.2%) and received tamoxifen + OFS (56.0 %). More European women had received chemotherapy (69.3 %). The characteristics of participants in the POSITIVE study provide insights to which patients and doctors considered it acceptable to interrupt ET to pursue pregnancy. Similarities and variations from a regional, sociodemographic, disease and treatment standpoint suggest specific sociocultural attitudes across the world.

Breast cancer (BC) is the most common cancer in women worldwide. Approximately 70–80% of BCs express estrogen receptors (ER), which predict the response to endocrine therapy (ET), and are therefore hormone receptor-positive (HR+). Endogenous cannabinoids together with cannabinoid receptor 1 and 2 (CB1, CB2) constitute the basis of the endocannabinoid system. Interactions of cannabinoids with hypothalamic–pituitary–gonadal axis hormones are well documented, and two studies found a positive correlation between peak plasma endogenous cannabinoid anandamide with peak plasma 17β-estradiol, luteinizing hormone and follicle-stimulating hormone levels at ovulation in healthy premenopausal women. Do cannabinoids have an effect on HR+ BC? In this paper we review known and possible interactions between cannabinoids and specific HR+ BC treatments. In preclinical studies, CB1 and CB2 agonists (i.e., anandamide, THC) have been shown to inhibit the proliferation of ER positive BC cell lines. There is less evidence for antitumor cannabinoid action in HR+ BC in animal models and there are no clinical trials exploring the effects of cannabinoids on HR+ BC treatment outcomes. Two studies have shown that tamoxifen and several other selective estrogen receptor modulators (SERM) can act as inverse agonists on CB1 and CB2, an interaction with possible clinical consequences. In addition, cannabinoid action could interact with other commonly used endocrine and targeted therapies used in the treatment of HR+ BC.

The paper assesses the dose-limiting toxicities and the maximum tolerated dose (MTD) of trastuzumab emtansine (T-DM1) combined with non-pegylated liposomal doxorubicin (NPLD) in HER2-positive (HER2+) metastatic breast cancer (MBC). This single-arm, open-label, phase Ib trial (NCT02562378) enrolled anthracycline-naïve HER2+ MBC patients who had progressed on trastuzumab and taxanes. Patients received a maximum of 6 cycles of NPLD intravenously (IV) at various dose levels (45, 50, and 60 mg/m²) in the “3 plus 3” dose-escalation part. During expansion, they received 60 mg/m² of NPLD every 3 weeks (Q3W) plus standard doses of T-DM1. The MTD was T-DM1 3.6 mg/kg plus NPLD 60 mg/m² administered IV Q3W. No clinically relevant worsening of cardiac function was observed. Among all evaluable patients, the overall response rate was 40.0% (95%CI, 16.3–67.7) with a median duration of response of 6.9 months (95%CI, 4.8–9.1). Clinical benefit rate was 66.7% (95%CI, 38.4–88.2) and median progression-free survival was 7.2 months (95%CI, 4.5–9.6). No significant influence of NPLD on T-DM1 pharmacokinetics was observed. The addition of NPLD to T-DM1 is feasible but does not seem to improve the antitumor efficacy of T-DM1 in HER2+ MBC patients.

Background: The treatment landscape in HR+/HER2− metastatic breast cancer (mBC) is continuously evolving, with evidence on new agents and combinations published almost every year. Despite updated therapeutic guidelines, second-line (2L) selection may be challenging due to clinical factors, biomarker status, and available agents. Methods: A two-round Delphi consensus was organized in July 2024, gathering input from 10 experts in research, diagnosis, and treatment of HR+/HER2− mBC on optimal 2L and beyond choice, considering the available biomarkers and results from published clinical trials. Consensus was defined as 70% agreement or disagreement. Results: The experts considered initially a list of 39 statements, structured into the following four sections: biomarker testing; selection of 2L treatment at progression of disease on first line endocrine therapy (ET) + CDK4/6i at ≥6 months after initiation of ET for mBC; selection of 2L treatment at disease progression on ET + CDK4/6i, at <6 months after initiation of ET for mBC, whilst on ET; and selection of post-2L treatment options. After a discussion, the experts decided to remove four statements, refine ten, and include three new ones. The final list consisted of 38 statements, and consensus was achieved in 37. Conclusions: The panel recommends next-generation sequencing as the method of choice for genomic characterization at disease progression on first line. The optimal agent or treatment class is indicated depending on the presence of specific mutations; however, the panel admits that the strategy is different in clinical practice, where novel therapies might not be available or reimbursed.