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Estrogen and progesterone receptor (ER, PR) signaling control breast development and impinge on breast carcinogenesis. ER is an established driver of ER + disease but the role of the PR, itself an ER target gene, is debated. We assess the issue in clinically relevant settings by a genetic approach and inject ER + breast cancer cell lines and patient-derived tumor cells to the milk ducts of immunocompromised mice. Such ER + xenografts were exposed to physiologically relevant levels of 17-β-estradiol (E2) and progesterone (P4). We find that independently both premenopausal E2 and P4 levels increase tumor growth and combined treatment enhances metastatic spread. The proliferative responses are patient-specific with MYC and androgen receptor (AR) signatures determining P4 response. PR is required for tumor growth in patient samples and sufficient to drive tumor growth and metastasis in ER signaling ablated tumor cells. Our findings suggest that endocrine therapy may need to be personalized, and that abrogating PR expression can be a therapeutic option. The role of progesterone receptor (PR) and its interplay with estrogen receptor (ER) in breast cancer is controversial. Here, the authors demonstrate that PR can have an ER-independent role in breast cancer growth and metastasis and that its effects are dependent on MYC and androgen receptor signatures.

Purpose At denosumab discontinuation, bone turnover markers increase and the gained BMD is lost. In postmenopausal osteoporosis, there is an increased risk of spontaneous vertebral fractures (VFs) of about 1 to 10%, rarely described in women under denosumab for aromatase inhibitors (AI)-treated breast cancer. We aim to describe the characteristics of 15 patients under denosumab given for AI-treated early-stage breast cancer that presented VFs at its discontinuation. Methods Single-center retrospective case series of 15 patients. We report clinical data, dual X-ray absorptiometry values at denosumab initiation and discontinuation, and serum B-crosslaps dosage at the time of VF occurrence (before denosumab resumption). Results Fifteen women (66.4 ± 7.1 years at denosumab discontinuation) that received AI for 5.0 ± 0.6 years, denosumab 60 mg for 8.2 ± 2.0 doses, and developed 60 VFs at denosumab discontinuation, were followed for 24.4 ± 9.5 months. Patients suffered from 1 to 11 (mean 4.0 ± 1.9) clinical VFs within 7 to 16 months after last denosumab injection. VFs developed earlier in patients with longer denosumab treatment ( R 2  = 0.29, p  = 0.04) and in patients without osteoporosis before denosumab (9.4 ± 2.0 vs. 13.0 ± 2.0 months; p  = 0.005). Serum B-crosslaps at the time of VFs tended to be higher in patients with earlier VFs ( R 2  = 0.47; p  = 0.06) or with longer denosumab treatment ( R 2  = 0.48; p  = 0.06). Denosumab was resumed in all patients, then switched for a bisphosphonate in eight. No new VFs occurred during follow-up. Conclusions Despite an apparently low fracture risk, women under denosumab for AI-treated early-stage breast cancer develop spontaneous VFs at denosumab discontinuation. This risk increases with treatment duration and may be prevented by a potent bisphosphonate.

Complementary medicine (CM) is used by one third to one half of cancer patients throughout the world. The objective of this study was to describe the prevalence of CM use and the potential for interactions with cancer treatments in an academic oncology centre. A cross-sectional study was conducted among patients undergoing current cancer treatment. Among 132 included patients, 56% had used CM since their cancer diagnosis and 45% were using CM during cancer treatment at the time of the survey. The main CM used were green tea (35%), herbal tea (35%), homeopathy (27%), dietary supplements (27%), and herbal medicines (27%). A small majority of patients (58%) spontaneously mentioned the use of CM to their oncologist. Of 42 identified combinations of concomitant use of biologically based CM and anticancer agents among the study patients, the potential for pharmacokinetic interactions of clinical relevance was not expected in 17 combinations (40%), hypothetical and deemed unlikely in 23 (55%), and of probable low clinical relevance in 2 (5%). Considering the high prevalence of CM use, active enquiries should be made by healthcare professionals to detect symptoms that may relate to CM tolerance and effects or that suggest interactions between CM and cancer treatments.

Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12 months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR). We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox). The payload consists of doxorubicin, a standard drug for TNBC. In a first-in-human phase I trial in 26 patients with various advanced solid malignancies, anti-EGFR-ILs-dox has shown little toxicity and encouraging efficacy. In this single-arm phase II trial, we assessed the efficacy of anti-EGFR-ILs-dox as first-line therapy in patients with advanced, EGFR + TNBC. The primary endpoint was progression-free survival at 12 months (PFS12m). Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to progression (TTP), overall survival (OS) and adverse events (AEs). 48 patients received anti-EGFR-ILs-dox 50 mg/m 2 iv, on day one of a 28 days-cycle until progression. The Kaplan–Meier estimate for PFS12m was 13% (one-sided 90% CI 7%, 95% CI [5%, 25%]), median PFS was 3.5 months (95% CI 1.9, 5.4). The trial has not reached its primary endpoint. There were no new toxicity signals. Based on these results, anti-EGFR-ILs-dox should not be further developed for TNBC. It remains an open question whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting this receptor has already shown anticancer effects. Trial registration: This trial was registered at clinicaltrials.gov: NCT02833766. Registered 14/07/2016.

Background Randomized trials have progressively enabled the de-escalation of axillary surgery in breast cancer (BC) patients, reducing adverse events without compromising survival. Despite a not negligible rate of residual disease in the axilla after sentinel lymph node (SLN) procedure, the risk of regional lymph node recurrence (RLNR) is very low, due probably to multimodal adjuvant treatments. The characteristics of the small number of patients with RLNR remain poorly characterized and warrant further investigation, especially given their poor prognosis and the current context of ongoing studies exploring further de-escalation of axillary surgery. Methods In this retrospective and single institution study, we analyzed thoroughly a cohort of patients who experienced RLNR as first event between 2009 and 2020. MammaPrint and BluePrint analysis (MB) was performed in available primary invasive cancer tissues. Results Forty patients, median age of 52, were analyzed. Disease-free interval was 8.7 years. Most of the patients (65%) had no special type BC. Majority (73%) had hormone receptor positive-HER2 negative (HR + /HER2−) BC, 13% triple negative (TNBC), 6% HER2 + , 8% ductal carcinoma in situ and 3% unknown. The median size of the primary tumor was 1.8 cm (range 0.3–7.0) and 57% had no initial LN involvement. Forty five percent had primary SLN procedure and 53% axillary LN dissection (ALND) of the patients received neo-/adjuvant chemotherapy, 63% endocrine therapy and 68% radiotherapy (50% only in breast). Sixty three percent had only RLNR and 38% had concomitant distant metastases. Among irradiated patients, 63% had some relapse in the radiation field. The MB analysis classified 70% of the analyzed cancers as low-risk luminal A (82% in HR + /HER2−), 15% high-risk luminal B, 10% high-risk basal type, and 5% high-risk HER2 type. Conclusion Our study confirms that patients treated with SLN do not show a higher risk of LRNR compared to ALND. LRNR is often diagnosed incidentally. Younger age, residual disease post-NAC, no regional radiation, stage II, and initial LN involvement were more represented, as well as patients with endocrine sensitive disease classified as low-risk luminal A by MB. Ongoing trials, including SOUND, INSEMA, and BOOG 2013-08, are further exploring axillary surgery de-escalation.

Background Treatment of patients with residual disease after neoadjuvant chemotherapy for breast cancer is an unmet clinical need. We hypothesised that tumour subclones showing expansion in residual disease after chemotherapy would contain mutations conferring drug resistance. Methods We studied oestrogen receptor and/or progesterone receptor-positive, HER2-negative tumours from 42 patients in the EORTC 10994/BIG 00-01 trial who failed to achieve a pathological complete response. Genes commonly mutated in breast cancer were sequenced in pre and post-treatment samples. Results Oncogenic driver mutations were commonest in PIK3CA (38% of tumours), GATA3 (29%), CDH1 (17%), TP53 (17%) and CBFB (12%); and amplification was commonest for CCND1 (26% of tumours) and FGFR1 (26%). The variant allele fraction frequently changed after treatment, indicating that subclones had expanded and contracted, but there were changes in both directions for all of the commonly mutated genes. Conclusions We found no evidence that expansion of clones containing recurrent oncogenic driver mutations is responsible for resistance to neoadjuvant chemotherapy. The persistence of classic oncogenic mutations in pathways for which targeted therapies are now available highlights their importance as drug targets in patients who have failed chemotherapy but provides no support for a direct role of driver oncogenes in resistance to chemotherapy. ClinicalTrials.gov EORTC 10994/BIG 1-00 Trial registration number NCT00017095.

TP53 has a crucial role in the DNA damage response. We therefore tested the hypothesis that taxanes confer a greater advantage than do anthracyclines on breast cancers with mutated TP53 than in those with wild-type TP53. In an open-label, phase 3 study, women (age <71 years) with locally advanced, inflammatory, or large operable breast cancers were randomly assigned in a 1:1 ratio to either a standard anthracycline regimen (six cycles of intravenous fluorouracil 500 mg/m 2, epirubicin 100 mg/m 2, and cyclophosphamide 500 mg/m 2 every 21 days [FEC100], or fluorouracil 600 mg/m 2, epirubicin 75 mg/m 2, cyclophosphamide 900 mg/m 2 [tailored FEC] starting on day 1 and then every 21 days) or a taxane-based regimen (three cycles of docetaxel 100 mg/m 2, intravenously infused over 1 h on day 1 every 21 days, followed by three cycles of intravenous epirubicin 90 mg/m 2 and docetaxel 75 mg/m 2 on day 1 every 21 days [T-ET]) at 42 centres in Europe. Randomisation was by use of a minimisation method that stratified patients by institution and initial tumour stage. The primary endpoint was progression-free survival (PFS) according to TP53 status. Analysis was by intention to treat. This is the final analysis of this trial. The study is registered with ClinicalTrials.gov, number NCT00017095. 928 patients were enrolled in the FEC group and 928 in the T-ET group. TP53 status was not assessable for 183 (20%) patients in the FEC group and 204 (22%) patients in the T-ET group mainly because of low tumour-cell content in the biopsy. 361 primary endpoint events were recorded in the FEC group and 314 in the T-ET group. In patients with TP53-mutated tumours, 5-year PFS was 59·5% (95% CI 53·4–65·1) in the T-ET group (n=326) and 55·3% (49·2–60·9) in the FEC group (n=318; hazard ratio 0·84, 98% CI 0·63–1·14; p=0·17). In patients with TP53 wild-type tumours, 5-year PFS was 66·8% (95% CI 61·4–71·6) in the T-ET group (n=398) and 64·7% (59·6–69·4) in the FEC group (n=427; 0·89, 98% CI 0·68–1·18; p=0·35). For all patients, irrespective of TP53 status, 5-year PFS was 65·1% (95% CI 61·6–68·3) in the T-ET group and 60·8% (57·3–64·2) in the FEC group (0·85, 98% CI 0·71–1·02; p=0·035). At the sites using FEC100 versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (75 [9%] of 803 vs 173 [21%] of 809, respectively), and neutropenia (653 [81%] vs 730 [90%], respectively). At the sites using tailored FEC versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (ten [8%] of 118 vs 26 [22%] of 116, respectively), and neutropenia (100 [85%] vs 115 [99%], respectively). Two patients died of toxicity during or within 30 days of chemotherapy completion and without disease relapse (one in each group). Although TP53 status was prognostic for overall survival, it was not predictive of preferential sensitivity to taxanes. TP53 status tested by use of the yeast assay in this patient population cannot be used to select patients for an anthracycline-based chemotherapy versus a taxane-based chemotherapy. US National Cancer Institute, La Ligue Nationale Contre le Cancer, European Union, Pharmacia, and Sanofi-Aventis.

Background The impact of HER2-targeted therapy alone followed by the addition of chemotherapy at disease progression (PD) versus upfront combination was investigated by the SAKK 22/99 trial. The aim of this exploratory analysis of the SAKK 22/99 trial was to characterize the specific subset of patients deriving long-term benefit from trastuzumab monotherapy alone and to identify potential predictive factors of long-term response. Methods This is an unplanned post-hoc analysis of patients randomized to Arm A (trastuzumab monotherapy). Patients were divided in two groups: patients with durable clinical benefit from trastuzumab monotherapy and short-term responders without durable clinical benefit from trastuzumab monotherapy Univariate and multivariate analyses of clinical characteristics correlating with response duration was performed. Results Eighty six patients were randomized in arm A, 24 patients (28%) were long-term responders and 62 (72%) were short-term responders with a 5y-overall survival (OS) of 54% (95% CI 31–72) and of 18% (95%CI 10–30), respectively. Absence of ER expression, absence of PgR expression and presence of visceral disease emerged as possible negative predictive factors for durable clinical benefit. Conclusion Durable clinical benefit can be achieved with trastuzumab monotherapy in a subgroup of HER2-positive patients with advanced disease and it is predictive for longer OS. Further investigations of predictive biomarkers are necessary to better characterize this subgroup of patients and develop further de-escalating strategies. Trial registration NCT00004935 ; first posted 27.01.2003, retrospectively registered.

Abstract Nervous system metastases (CNSm) are late events associated with poor outcomes in endocrine-sensitive HER2-negative breast cancer (BC) patients, especially in the presence of leptomeningeal disease (LMD). Effective treatments are extremely limited in this setting. The antibody-drug conjugate, trastuzumab-deruxtecan (T-DXd), which combines the anti-HER2 antibody trastuzumab with a topoisomerase type 1 inhibitor, showed high efficacy not only against HER2-positive but also HER2-low metastatic BCs, expressing HER2 at a lower level. To the best of our knowledge, this is the first report of a patient with metastatic endocrine-sensitive HER2-low BC suffering from BMs associated with LMD and sustained disease control when treated with T-DXd. Several recent case series have reported the activity of T-DXd in patients with HER2-positive disease and brain metastases or LMD, but none in HER2-low patients. This case is particularly relevant since more than 50% of BCs are HER2-low.

Letrozole radiosensitises breast cancer cells in vitro. In clinical settings, no data exist for the combination of letrozole and radiotherapy. We assessed concurrent and sequential radiotherapy and letrozole in the adjuvant setting. This phase 2 randomised trial was undertaken in two centres in France and one in Switzerland between Jan 12, 2005, and Feb 21, 2007. 150 postmenopausal women with early-stage breast cancer were randomly assigned after conserving surgery to either concurrent radiotherapy and letrozole (n=75) or sequential radiotherapy and letrozole (n=75). Randomisation was open label with a minimisation technique, stratified by investigational centres, chemotherapy (yes vs no), radiation boost (yes vs no), and value of radiation-induced lymphocyte apoptosis (≤16% vs >16%). Whole breast was irradiated to a total dose of 50 Gy in 25 fractions over 5 weeks. In the case of supraclavicular and internal mammary node irradiation, the dose was 44–50 Gy. Letrozole was administered orally once daily at a dose of 2·5 mg for 5 years (beginning 3 weeks pre-radiotherapy in the concomitant group, and 3 weeks post-radiotherapy in the sequential group). The primary endpoint was the occurrence of acute (during and within 6 weeks of radiotherapy) and late (within 2 years) radiation-induced grade 2 or worse toxic effects of the skin. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00208273. All patients were analysed apart from one in the concurrent group who withdrew consent before any treatment. During radiotherapy and within the first 12 weeks after radiotherapy, 31 patients in the concurrent group and 31 in the sequential group had any grade 2 or worse skin-related toxicity. The most common skin-related adverse event was dermatitis: four patients in the concurrent group and six in the sequential group had grade 3 acute skin dermatitis during radiotherapy. At a median follow-up of 26 months (range 3–40), two patients in each group had grade 2 or worse late effects (both radiation-induced subcutaneous fibrosis). Letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy. Long-term follow-up is needed to investigate cardiac side-effects and cancer-specific outcomes. Novartis Oncology France.