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Resistance to endocrine therapies in hormone receptor-positive breast cancer is challenging. We aimed to assess the next-generation oral selective oestrogen receptor degrader (SERD) and complete oestrogen receptor antagonist, camizestrant, versus the first-approved SERD, fulvestrant, in post-menopausal women with oestrogen receptor-positive, HER2-negative, advanced breast cancer. SERENA-2 is an open-label, randomised, phase 2 trial that is being conducted at 74 study centres across Asia, Europe, the Middle East, and North America. Female patients aged 18 years or older who were post-menopausal with histologically or cytologically confirmed metastastic or locoregional oestrogen receptor-positive, HER2-negative breast cancer, an Eastern Cooperative Oncology Group or WHO performance status of 0 or 1, and disease recurrence or progression on at least one line of endocrine therapy, and no more than one previous endocrine therapy in the advanced setting. Patients were initially randomly assigned (1:1:1:1) to receive oral camizestrant once daily at 75 mg, 150 mg, or 300 mg (until the 300 mg group was closed), or fulvestrant intramuscularly at 500 mg (per label). Randomisation was managed through an interactive web-based system and stratified by previous treatment with CDK4/6 inhibitors and presence of liver and/or lung metastases. The primary objective was to determine clinical efficacy of camizestrant versus fulvestrant at each dose level using the primary endpoint of investigator-assessed progression-free survival, per Response Evaluation Criteria in Solid Tumours (version 1.1), assessed by intention to treat in all randomly assigned patients (full analysis set). No formal statistical comparison for the efficacy analysis of the camizestrant 300 mg dose versus fulvestrant was to be performed. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04214288, and is ongoing. Between May 11, 2020, and Aug 10, 2021, 240 patients were randomly assigned to receive camizestrant 75 mg (n=74), 150 mg (n=73), 300 mg (n=20), or fulvestrant (n=73), and were included in the full analysis set. All patients received at least one dose of study drug. Median follow-up was 16·6 months (IQR 12·9–19·4) for the camizestrant 75 mg group, 16·3 months (12·9–18·3) for the camizestrant 150 mg group, and 14·7 months (12·7–20·1) for the fulvestrant 500 mg group. Median progression-free survival was 7·2 months (90% CI 3·7–10·9) with camizestrant 75 mg, 7·7 months (5·5–12·9) with camizestrant 150 mg, and 3·7 months (2·0–6·0) with fulvestrant. The hazard ratio for camizestrant 75 mg versus fulvestrant was 0·59 (90% CI 0·42–0·82; p=0·017), and the hazard ratio for camizestrant 150 mg versus fulvestrant was 0·64 (0·46–0·89; p=0·0090). Treatment-related adverse events occurred in 39 (53%) of 74 patients in the camizestrant 75 mg group, 49 (67%) of 73 patients in the camizestrant 150 mg group, 14 (70%) of 20 patients in the camizestrant 300 mg group, and 13 (18%) of 73 patients in the fulvestrant group. No single grade 3 or worse treatment-emergent adverse event occurred in more than two (3%) patients in any group. Serious treatment-emergent adverse events occurred in six (8%) patients in the camizestrant 75 mg group, seven (10%) patients in the camizestrant 150 mg group, two (10%) patients in the camizestrant 300 mg group, and four (5%) patients in the fulvestrant group. No treatment-related deaths occurred. Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor-positive, HER2-negative breast cancer. AstraZeneca.

Among patients with metastatic breast cancer with low HER2 expression, treatment with trastuzumab deruxtecan prolonged progression-free survival as compared with the physician’s choice of chemotherapy.

In women with hormone-receptor–positive metastatic breast cancer that had progressed after endocrine therapy, palbociclib plus fulvestrant was associated with progression-free survival of more than 9 months, as compared with less than 4 months with fulvestrant alone. Approximately 80% of breast cancers express estrogen receptors, progesterone receptors, or both. Endocrine therapies are the mainstay of treatment for these hormone-receptor–positive cancers, substantially reducing the relapse rate after presentation with early-stage cancer. 1 Despite advances in endocrine therapy, many women have a relapse during or after completing adjuvant therapy. The care of these women remains a considerable clinical challenge. Single-agent treatment with an aromatase inhibitor or tamoxifen has shown limited clinical benefit. 2 , 3 The selective estrogen-receptor degrader fulvestrant has modest activity in this population of patients, 4 , 5 and the development of effective therapies that can reverse resistance to endocrine therapy . . .

In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1mut), while assessing the global safety of combination fulvestrant and palbociclib. We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited and monitored for rising bESR1mut during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1–21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete. From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2–41·4) from inclusion and 26·0 months (13·8–34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1–13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9–7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43–0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 [70·3%] of 1017 patients), lymphopenia (66 [6·5%]), and thrombocytopenia (20 [2·0%]). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 [41·7%] of 84 patients in the aromatase inhibitor and palbociclib group vs 39 [44·3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3·6%] vs four [4·5%]). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related. PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials. Pfizer.

Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants. Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67–0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 [95% CI 0·68–0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 [0·60–0·97], one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. Novartis Pharmaceuticals Corporation.

Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0–2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380. Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0·797, 95% CI 0·637–0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83–20·99) in the fulvestrant group versus 13·8 months (11·99–16·59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients. AstraZeneca.

Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose tissue predominantly in the lower body. The onset of lipedema pathophysiology is thought to occur during periods of hormonal fluctuation, such as puberty, pregnancy, or menopause. Although the identification and characterization of lipedema have improved, the underlying disease etiology remains to be elucidated. Estrogen, a key regulator of adipocyte lipid and glucose metabolism, and female-associated body fat distribution are postulated to play a contributory role in the pathophysiology of lipedema. Dysregulation of adipose tissue accumulation via estrogen signaling likely occurs by two mechanisms: (1). altered adipocyte estrogen receptor distribution (ERα/ERß ratio) and subsequent metabolic signaling and/or (2). increased release of adipocyte-produced steroidogenic enzymes leading to increased paracrine estrogen release. These alterations could result in increased activation of peroxisome proliferator-activated receptor γ (PPARγ), free fatty acid entry into adipocytes, glucose uptake, and angiogenesis while decreasing lipolysis, mitochondriogenesis, and mitochondrial function. Together, these metabolic alterations would lead to increased adipogenesis and adipocyte lipid deposition, resulting in increased adipose depot mass. This review summarizes research characterizing estrogen-mediated adipose tissue metabolism and its possible relation to excessive adipose tissue accumulation associated with lipedema.

Among women with previously untreated hormone-receptor–positive advanced breast cancer, the addition of the cyclin-dependent kinase inhibitor palbociclib to letrozole therapy resulted in longer progression-free survival than that with letrozole alone. Hormone-receptor–positive breast cancer represents the largest therapeutic subtype of the disease, accounting for 60 to 65% of all malignant neoplasms of the breast. For more than 50 years, the treatment of hormone-receptor–positive disease has been focused on targeting the estrogen-receptor signaling pathway. 1 However, both new and acquired resistance to hormonal blockade occurs in a large subset of these cancers, and new approaches are needed. 2 The cyclin-dependent kinases (CDKs) are a large family of serine–threonine kinases that play an important role in regulating cell-cycle progression. The interaction of cyclin D with CDK4 and CDK6 facilitates the hyperphosphorylation of the retinoblastoma (Rb) . . .

SummaryBackgroundOral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer. MethodsWe did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20–75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80–120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969. FindingsBetween Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1–58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49–0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [<1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (<1%) of 970 patients in the endocrine therapy alone group and 23 (2%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis. InterpretationThese data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer. FundingPublic Health Research Foundation (Japan), Taiho Pharmaceutical.

For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (688 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·78). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·75 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.