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Phosphoproteomics is a promising tool for identifying biomarkers of treatment response in cancer. Here, the authors analyse proteomics profiling of HER2-negative female breast cancer patients and identify potential predictors of paclitaxel response.

Neoadjuvant endocrine therapy (NET) for hormone receptor-positive (HR+) breast cancer might be as effective as chemotherapy, with a better toxicity profile. Blocking a crucial process such as angiogenesis with sunitinib may have a synergistic effect with NET. We aimed to assess the efficacy and safety of neoadjuvant sunitinib plus exemestane in early-stage HR+/HER2-negative breast cancer. In this phase I/II study, postmenopausal women with HR+/HER2- stage II-III breast cancer received neoadjuvant exemestane at conventional dose of 25mg plus sunitinib in a 3 + 3 design at 25mg (3/1weeks scheme) or 37.5mg continuous dose, for 6 months. Coprimary endpoints were the recommended dose of sunitinib combined with exemestane and objective response. Secondary endpoints included safety and biomarkers of early response. For 15 months, 18 patients were enrolled, 15 at sunitinib 25mg and 3 at 37.5mg. Median age was 73, 77% of patients had T2 tumors and 67% node-positive disease. The most common grade 2 toxicity was asthenia (44%), as was hypertension (22%) for grade 3. No grade 4-5 were reported. Twelve patients (66%) achieved an objective response. VEGFR-2 levels significantly decreased after one month of treatment. Differential gene expression analysis showed downregulation of ESR1, PGR and NAT1 in post-treatment samples and upregulation of EGFR, MYC, SFRP1, and FOXC1. PAM50 analysis on 83% of patients showed a prevalence of luminal A subtype, both in pre-treatment (63.6%) and post-treatment tumors (54.5%). Sunitinib plus exemestane was associated with substantial yet reversible toxicities, providing safety, efficacy and biological impact insights of combining an antiangiogenic drug with hormone therapy in early-stage breast cancer.Trial registration: Registered with ClinicalTrials.gov, NCT00931450. 02/07/2009., (© 2024. The Author(s).)

Background: The effect of the addition of cyclin-dependent kinases 4 and 6 inhibitors to endocrine therapy in terms of molecular downstaging remains undetermined. Switching from a high-risk to a low risk Recurrence Score (RS) group could provide useful information to identify patients who might not require chemotherapy. The purpose of this study was to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment for patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with an initial Oncotype DX RS ≥18., Patients and Methods: Participants were women aged ≥18 years with HR-positive/HER2-negative, Ki67 ≥ 20%, stage II-IIIB early breast cancer with a baseline RS ≥18. Eligible patients with a pretreatment RS 18-25 (cohort A) and 26-100 (cohort B) received six 28-day cycles of letrozole (2.5 mg per day; plus goserelin if pre- or perimenopausal) plus palbociclib (125 mg per day; 3/1 schedule) before surgery. The primary endpoint for both cohorts was the proportion of patients who achieved an RS ≤25 at surgery or a pathological complete response (pCR)., Results: A total of 67 patients were enrolled, among which 65 were assessable for the primary endpoint (32 patients in cohort A and 33 in cohort B). At surgery, 22 (68.8%) patients in cohort A and 18 (54.5%) patients in cohort B had an RS ≤25 or a pCR [only 1 (3.0%) patient in cohort B], meeting the primary endpoint in cohort B (P < 0.01), but not in cohort A (P = 0.98). No new safety signals were identified., Conclusions: The efficacy of neoadjuvant treatment with letrozole plus palbociclib does not seem to depend on pretreatment RS for patients with RS ≥18. However, around half of patients with HR-positive/HER2-negative early breast cancer with an RS 26-100 at baseline achieved molecular downstaging with this regimen., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Cyclin-dependent kinases 4/6 inhibitors (CDK 4/6i) combined with endocrine therapy have become the gold standard in hormone receptor-positive (HR +) HER2-negative (HER2-) metastatic breast cancer (MBC). However, there is a significant lack of data regarding the efficacy and safety of these treatments in elderly patients. We present the results of a real-world data (RWD) cohort stratified by age at treatment initiation (≥ 70 years compared to patients < 70 years)., Methods: Clinico-pathological data of HR + HER2- MBC patients who were candidates for CDK4/6i therapy between January 2017 and December 2020 at the Institut Català d'Oncologia (Spain) were retrospectively collected. The primary goal was to assess Progression-Free Survival (PFS), Overall Survival (OS), and safety outcomes within this patient population., Results: A total of 274 patients with MBC who received CDK4/6i treatment were included in the study. Among them, 84 patients (30.8%) were aged ≥ 70 years, with a mean age of 75, while 190 patients (69.2%) were under the age of 70, with a mean age of 55.7 years. The most frequently observed grade 3-4 toxicity was neutropenia, with similar rates in both the < 70 group (43.9%) and the ≥ 70 group (47.9%) (p = 0.728). The median Progression-Free Survival (mPFS) for the first-line CDK4/6i treatment was 22 months (95% CI, 15.4-39.8) in the < 70 group and 20.8 months (95% CI 11.2-NR) in the ≥ 70 group (p = 0.67). Similarly, the median PFS for the second-line CDK4/6i treatment was 10.4 months (95% CI, 7.4-15.1) and 7.1 months (95% CI 4.4-21.3) (p = 0.79), respectively. Median overall survival (mOS) was not reached either for the first- and second-line treatment., Conclusions: Our RWD suggests that elderly patients, when compared to those under 70, experience similar survival outcomes and exhibit comparable tolerance for CDK4/6i therapy., (© 2024. The Author(s).)

Introduction : Neoadjuvant chemotherapy in breast cancer offers the possibility to facilitate breast and axillary surgery; it is a test of chemosensibility in vivo with significant prognostic value and may be used to tailor adjuvant treatment according to the response. Material and Methods : A retrospective single-institution cohort of 482 stage II and III breast cancer patients treated with neoadjuvant chemotherapy based on anthracycline and taxans, plus antiHEr2 in Her2-positive cases, was studied. Survival was calculated at 5 and 10 years. Kaplan-Meier curves with a log-rank test were calculated for differences according to age, BRCA status, menopausal status, TNM, pathological and molecular surrogate subtype, 20% TIL cut-off, surgical procedure, response to chemotherapy and the presence of vascular invasion. Results : The pCR rate was 25.3% and was greater in HER2 (51.3%) and TNBC (31.7%) and in BRCA carriers (41.9%). The factors independently related to patient survival were pathology and molecular surrogate subtype, type of surgery, response to NACT and vascular invasion. BRCA status was a protective prognostic factor without reaching statistical significance, with an HR 0.5 (95%CI 0.1-1.4). Mastectomy presented a double risk of distant recurrence compared to breast-conservative surgery (BCS), supporting BCS as a safe option after NACT. After a mean follow-up of 126 (SD 43) months, luminal tumors presented a substantial difference in survival rates calculated at 5 or 10 years (81.2% compared to 74.7%), whereas that for TNBC was 75.3 and 73.5, respectively. The greatest difference was seen according to the response in patients with pCR, who exhibited a 10 years DDFS of 95.5% vs. 72.4% for those patients without pCR, p < 0001. This difference was especially meaningful in TNBC: the 10 years DDFS according to an RCB of 0 to 3 was 100%, 80.6%, 69% and 49.2%, respectively, p < 0001. Patients with a particularly poor prognosis were those with lobular carcinomas, with a 10 years DDFS of 42.9% vs. 79.7% for ductal carcinomas, p = 0.001, and patients with vascular invasion at the surgical specimen, with a 10 years DDFS of 59.2% vs. 83.6% for those patients without vascular invasion, p < 0.001. Remarkably, BRCA carriers presented a longer survival, with an estimated 10 years DDFS of 89.6% vs. 77.2% for non-carriers, p = 0.054. Conclusions : Long-term outcomes after neoadjuvant chemotherapy can help patients and clinicians make well-informed decisions.

In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection. Results showed that at surgery, Ki67 and the PAM50 proliferation scores were lower after ribociclib compared to chemotherapy. However, consistent reactivation of tumor cell proliferation from day 14 to surgery was only observed in the ribociclib arm. In tumors with complete cell cycle arrest (CCCA) at surgery, PAM50 proliferation scores were lower in the ribociclib arm compared to chemotherapy (p < 0.001), whereas the opposite was observed with tumor cellularity (p = 0.002). Gene expression signatures (GES) associated with antigen-presenting cells (APCs) and innate immune system activity showed increased expression post-chemotherapy but decreased expression post-ribociclib. Interferon-associated GES had decreased expression with CCCA and increased expression with non-CCCA. Our findings suggest that while both treatment strategies decreased proliferation, the depth and the patterns over time differed by treatment arm. Immunologically, ribociclib was associated with downregulated GES associated with APCs and the innate immune system in Luminal B tumors, contrary to existing preclinical data. Further studies are needed to understand the effect of CDK4/6 inhibition on the tumor cells and microenvironment, an effect which may vary according to tumor subtypes., (© 2024. The Author(s).)

Purpose: Prognostic and predictive biomarkers to cyclin-dependent kinases 4 and 6 inhibitors are lacking. Circulating tumor DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy., Experimental Design: Correlative blood samples were collected at baseline [cycle 1-day 1 (C1D1)] and prior to treatment [cycle 1-day 15 (C1D15)]. Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A prespecified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model., Results: 201 patients were profiled at baseline, with ctDNA detection associated with worse progression-free survival (PFS)/overall survival (OS). Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n = 120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms., Conclusions: We show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with hormone receptor-positive/HER2-negative metastatic breast cancer harboring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted., (©2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: Breast cancer surgery currently focuses on de-escalating treatment without compromising patient survival. Axillary radiotherapy (ART) now replaces axillary lymph node dissection (ALND) in patients with limited sentinel lymph node (SLN) involvement during the primary surgery, and this has significantly reduced the incidence of lymphedema without worsening the prognosis. However, patients treated with neoadjuvant systemic treatment (NST) cannot benefit from this option despite the low incidence of residual disease in the armpit in most cases. Data regarding the use of radiotherapy instead of ALND in this population are lacking. This study will assess whether ART is non-inferior to ALND in terms of recurrence and overall survival in patients with positive SLN after NST, including whether it reduces surgery-related adverse effects., Methods and Analyses: This multicenter, randomized, open-label, phase 3 trial will enroll 1660 patients with breast cancer and positive SLNs following NST in approximately 50 Spanish centers over 3 years. Patients will be stratified by NST regimen and nodal involvement (isolated tumoral cells or micrometastasis versus macrometastasis) and randomly assigned 1:1 to ART without ALND (study arm) or ALND alone (control arm). Level 3 and supraclavicular radiotherapy will be added in both arms. The primary outcome is the 5-year axillary recurrence determined by clinical and radiological examination. The secondary outcomes include lymphedema or arm dysfunction, quality of life based (EORTC QLQ-C30 and QLQ-BR23 questionnaires), disease-free survival, and overall survival., Discussion: This study aims to provide data to confirm the efficacy and safety of ART over ALND in patients with a positive SLN after NST, together with the impact on morbidity., Ethics and Dissemination: The Research Ethics Committee of Bellvitge University Hospital approved this trial (Protocol Record PR148/21, version 3, 1/2/2022) and all patients must provide written informed consent. The involvement of around 50 centers across Spain will facilitate the dissemination of our results., Trial Registration: ClinicalTrials.gov, identifier number NCT04889924., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Garcia-Tejedor, Ortega-Exposito, Salinas, Luzardo-González, Falo, Martinez-Pérez, Pérez-Montero, Soler-Monsó, Bajen, Benitez, Ortega, Petit, Guma, Campos, Plà, Pernas, Peñafiel, Yeste, Gil-Gil, Guedea, Ponce and Laplana.)

Purpose: Data on the benefit of stereotactic body radiation therapy (SBRT) in patients with breast cancer (BC) and bone metastases remain limited. The purpose of this study is to report our 10-year experience of bone SBRT, analyzing toxicity and prognostic factors for local control (LC); progression-free survival, and overall survival (OS)., Methods/patients: We analyzed all spine and non-spine bone SBRT performed in patients with BC during the 2012-2022 period at our institution. Treatments carried out with ablative intent in stereotactic conditions with dose/fraction ≥ 5 Gy in 5 or fewer sessions were considered. Demographic, treatment, and toxicity data were recorded according to CTCAEv4. Risk factors were assessed through univariate and multivariate analysis by Cox regression., Results: 60 bone SBRT treatments were performed during the study period. 75% were spine SBRT and 25% were non-spine SBRT (median BED 4 Gy was 80 Gy 4 ). The median age was 52.5 years (34-79). The median tumor volume was 2.9 cm 3 (0.5-39.4). The median follow-up was 32.4 months (1.2-101.7). 1 and 2 years LC were 92.9 and 86.6%, respectively. 1 and 2 years OS were 100 and 90.6%, respectively. Multivariate analysis (MVA) associated volume of the treated lesion ≥ 13 cm 3 with worse LC (p = 0.046; HR 12.1, 95%CI = 1.1-140.3). In addition, deferring SBRT > 3 months after lesion diagnosis to prioritize systemic treatment showed a significant benefit, improving the 2 years LC up to 96.8% vs. 67.5% for SBRT performed before this period (p = 0.031; HR 0.1, 95%CI = 0.01-0.8). Hormonal receptors, the total number of metastases, and CA15-3 value were significantly associated with OS in MVA. During follow-up, three non-spine fractures (5%) were observed., Conclusions: According to our data, bone SBRT is a safe and effective technique for BC. Upfront systemic treatment before SBRT offers a benefit in LC. Therefore, SBRT should be considered after prior systemic treatment in this population., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Purpose: To evaluate the differences in nodal positivity if the sentinel lymph node biopsy (SLNB) is performed before or after neoadjuvant endocrine therapy (NET) in breast cancer patients, and its impact on prognosis., Methods: A retrospective cohort study was performed in a single center including 91 postmenopausal cases with clinically node-negative and hormone receptor-positive/HER2-negative (HR + /HER2-) breast cancer, treated with NET and SLNB. SLNB was done pre-NET until 2014, and post-NET thereafter. Axillary lymph node dissection (ALND) was indicated only in SLNB macrometastasis, although in selected elderly patients, it was omitted. Kaplan-Meier survival curves were estimated in relation to the status of the axilla, and the differences assessed using the log-rank test., Results: Between December 2006 and March 2022, SLNB was performed pre-NET in 14 cases and post-NET in 77. Both groups were similar in baseline tumor and patient characteristics. SLNB positivity was similar regardless of whether SLNB was performed before (5/14, 35.7%) or after NET (27/77, 37%), with 2/14 SLN macrometastases in the pre-NET cohort and 17/77 in the post-NET cohort. Only three patients (18.7%) with SLN macrometastasis had > 3 positive nodes following ALND. The 5-year overall survival and distant disease-free survival were 92.4% and 94.8%, respectively, with no significant differences according to SLNB status (p 0.5 and 0.8, respectively)., Conclusion: SLN positivity did not differ according to its timing (before or after NET). Therefore, NET has no effect on lymph node clearance. Furthermore, the prognosis is good regardless of the axillary involvement. Therefore, factors other than axillary involvement may affect the prognosis in these patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim and Objectives: To assess the adherence of a nursing care model in a multidisciplinary breast cancer unit in a tertiary hospital to the recommended competencies and quality indicators., Background: Aligning the competencies of the breast care nurse with international recommendations for this role helps better fulfil patient needs, increases satisfaction and ensures continuity of care., Design: Cohort study., Methods: Breast care nursing was assessed in all patients treated at the Functional Breast Unit from 1 July 2016 to 30 June 2017. Patients were followed for 1 year. Sociodemographic, clinical and pathological data, treatments performed and nursing interventions were collected. The strobe checklist has been used to report this study., Results: We analysed nursing interventions carried out in 382 patients attended over 1 year in a multidisciplinary breast cancer unit. All patients with early disease had contact with the nurse at different times during their primary treatment. Only 58% of patients with advanced disease had contact with the nurse during their first year of illness. Moreover, first contact with the nurse was delayed by more than a week from diagnosis, the interval recommended by international guidelines., Conclusion: The nursing care model meets the core competencies defined for the breast care nurse in patients with early breast cancer, but the first visit should be organised earlier, and follow-up should extend beyond completion of primary treatment., Relevance to Clinical Practice: This study evaluated the breast care nurse model in one breast cancer unit according to international guidelines. Nursing care adhered to most guideline requirements in patients with early breast cancer, but not in those with advanced disease. New models of care need to be developed for women with advanced breast cancer in order to achieve true patient-centred care., Patient or Public Contribution: No contribution from the patient or the public because the data collected was entered into the clinical history by the health professionals of the Breast Unit as part of their usual clinical practice., (© 2023 The Authors. Journal of Clinical Nursing published by John Wiley & Sons Ltd.)

Purpose: In hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting, but further validation is needed., Experimental Design: We performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HR+/HER2- MBC to receive palbociclib+endocrine therapy (ET) versus capecitabine. Estrogen receptor-positive (ER+)/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET., Results: Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4 months with palbociclib+ET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclib+ET (6.2 months) than with capecitabine (9.3 months); HR 1.55, adjusted P value = 0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile), we found higher levels of Polo-like kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models, we show that PLK1 inhibition reverses resistance to palbociclib+ET., Conclusions: We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (ABC)., Patients and Methods: The multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis., Results: Among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6-53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2-27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8-6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71-282.9; P = 0.018)., Conclusions: Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials., (©2022 The Authors; Published by the American Association for Cancer Research.)

Precision oncology research is challenging outside the contexts of oncogenic addiction and/or targeted therapies. We previously showed that phosphoproteomics is a powerful approach to reveal patient subsets of interest characterized by the activity of a few kinases where the underlying genomics is complex. Here, we conduct a phosphoproteomic screening of samples from HER2-negative female breast cancer receiving neoadjuvant paclitaxel (N = 130), aiming to find candidate biomarkers of paclitaxel sensitivity. Filtering 11 candidate biomarkers through 2 independent patient sets (N = 218) allowed the identification of a subgroup of patients characterized by high levels of CDK4 and filamin-A who had a 90% chance of achieving a pCR in response to paclitaxel. Mechanistically, CDK4 regulates filamin-A transcription, which in turn forms a complex with tubulin and CLIP-170, which elicits increased binding of paclitaxel to microtubules, microtubule acetylation and stabilization, and mitotic catastrophe. Thus, phosphoproteomics allows the identification of explainable factors for predicting response to paclitaxel., (© 2022. The Author(s).)

Introduction: In the phase II CORALLEEN trial, patients with PAM50 luminal B early breast cancer (EBC) were randomised to neoadjuvant ribociclib plus letrozole (R + L) or chemotherapy based on anthracyclines and taxanes. Results from the primary efficacy analysis showed a similar proportion of patients with response at surgery in both groups. How health-related quality of life (HRQoL) outcomes with R + L compare with chemotherapy in EBC setting is still unknown. Here, we report the results of the HRQoL analysis from the CORALLEEN study., Methods: A total of 106 women were randomised 1:1 to receive neoadjuvant R + L (n = 52) or chemotherapy (n = 54). Patient-reported outcomes were assessed using two questionnaires: EORTC QLQ-C30 and EORTC QLQ-BR23. Change from baseline in the global health status, functional, and symptom scales was analysed using linear mixed-effect models, and between-treatment differences were estimated along with 95% confidence interval (95% CI)., Results: At baseline, the overall questionnaire available rate was 94.3%, and patient-reported outcomes were similar between treatment groups. At the end of the study treatment (24 weeks), patients receiving R + L showed better global health status scores with a between-treatment difference of 17.7 points (95% CI 9.2-26.2; p-value &lt;0.001). The R + L group also presented numerically better outcomes in all functional and symptom scales. The larger between-treatment differences in symptom severity were found in fatigue (-28.9; 95% CI -38.5 to -19.3), appetite loss (-23; 95% CI -34.9 to -11.2) and systematic therapy side-effects (-11.4; 95% CI -18.3 to -4.6)., Conclusions: Neoadjuvant R + L was associated with better HRQoL outcomes compared with chemotherapy in patients with luminal B EBC., Registration Identification: ClinicalTrials.gov Identifier: NCT03248427., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: G. Villacampa: Consulting Fees (e.g. advisory boards); AstraZeneca. Other (speakers' bureaus); MSD, GSK and Pierre Fabre. C. Falato: Contracted Research; Fellowship from the Swedish Society for Medical Research. L. Paré: Receipt of Intellectual Property Rights/Patent Holder; HER2DX filing. C. Hernando: None declared. M. Arumí: Other; Roche, Eisai, MSD. C. Saura: Consulting Fees (e.g. advisory boards); Astrazeneca, Daiichi Sankyo, Exact Sciences, MSD, Philips, Pierre-Fabre, Puma Biotechnology, Roche, SeaGen, Zymeworks. Other (Consultant); Astrazeneca, AX'S Consulting sprl, Byondis B.V, Eisai, Exeter Pharma, Roche, MediTech, Novartis, Pfizer, Pierre Fabre, PintPharma and SeaGen. G. Gomez Melis: None declared. M. Muñoz: Consulting Fees (e.g. advisory boards); Pierre Fabre. Other; Eisai, Lilly, Novartis, Pfizer, Roche. M. Gil-Gil: Consulting Fees (e.g. advisory boards); AstraZeneca, Agendia. Other; Pfizer, Roche, Novartis, Pierre-Faber, Daiichi-Sankyo, Eisai. Y. Izarzugaza: Consulting Fees (e.g. advisory boards); Novartis. Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers' bureaus); Novartis, Pfizer. N. Ferrer: None declared. J. Najera-Zuloaga: None declared. A. Montaño: None declared. E. Ciruelos: Consulting Fees (e.g. advisory boards); Pfizer, Daiichi Sankyo, Novartis, MSD, AstraZeneca, Roche, Lilly. Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers' bureaus); Roche, Lilly. S. González-Santiago: Consulting Fees (e.g. advisory boards); Roche, Lilly, MSD, Pharmamar, Clovis, Pfizer. Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers' bureaus); Novartis, GSK, MSD, Pfizer. P. Villagrasa: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers' bureaus); Summit NS ESMO 2019 speaker. Other; Oncolytics. J. Gavilá: Consulting Fees (e.g. advisory boards); Lilly, AstraZeneca, Novartis, Pfizer, Roche. Other; AstraZeneca, Lilly, Novartis, Pfizer, Roche. A. Prat: Salary; Pfizer, Roche, Lilly, Amgen, Novartis, MSD Oncology, Daiichi Sankyo, Guardant Health. Receipt of Intellectual Property Rights/Patent Holder; PCT/EP2016/080056: HER2 AS A PREDICTOR OF RESPONSE TO DUAL HER2 BLOCKADE IN THE ABSENCE OF CYTOTOXIC THERAPY, WO/2018/096191. Chemoendocrine score (CES) Based on PAM50 for breast cancer with positive hormone receptors with an intermediate risk of recurrence, METHODS FOR BREAST CANCER TREATMENT AND PREDICTION OF THERAPEUTIC RESPONSE (US 63/023785), HER2DX filing. Consulting Fees (e.g. advisory boards); Amgen, Novartis, Bristol-Myers Squibb, PUMA, Daiichi Sankyo, Astrazeneca, Roche, Pfizer, Boehringer, Oncolytics Biotech, Abbvie, NanoString Technologies. Contracted Research; Roche, Novartis, Incyte, Puma Biotechnology. Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds); Reveal Genomics. Other; Oncolytics, Daiichi Sankyo, Peptomyc SL. T. Pascual: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers' bureaus); AstraZeneca, Pfizer. Consulting Fees (e.g. advisory boards); Novartis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The Epi-GEICAM study comprises 1017 invasive BC cases matched with controls of similar age (49 ± 9 years) and residence. Diet and OO consumption were collected through a validated food frequency questionnaire. 75% of women referred OO, common (refined) or virgin, as the main fat source. Using conditional logistic regression models, we compared different scenarios of type and frequency of OO consumption, using as reference those women not always using OO for the three culinary practices (seasoning, cooking, and frying) and adding <2 tablespoons (tbsps.) per day during the meal to bread, salad, or dishes. A substantial inverse association was observed in those women always using VOO for the three culinary practices and consuming ≥2 tbsps. of OO per day during meals (adjusted OR, 0.72; 95% CI: 0.51, 1.03; P = 0.07). Potential benefits from OO consumption, at least as regards the protection provided for BC, could be mostly conferred with VOO, and when its consumption is high., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Metaplastic breast carcinomas are a rare and heterogeneous group of tumors (0.5-2%). They are mainly triple negative tumors but they present poorer chemotherapy responses and worse prognosis than other triple negative tumors. The aim of our study was to characterize the molecular profile and tumor evolution in matched (primary-relapse) tumor samples from patients with early-stage metaplastic breast carcinomas who had disease recurrence/progression. We performed genomic profiling of tumor biopsies at least from two different time points of their tumor evolution. Tumor samples were analyzed by DNA-Next Generation Sequencing (Illumina 2 x 75bp) using the Action OncoKitDX panel (Imegen-Health in Code group), which includes point mutations in 50 genes, CNVs, and fusion genes. Only pathogenic and likely pathogenic variants were considered for analysis and they were categorized following the ComPerMed criteria. We analyzed 21 matched tumor samples (8 primary and 13 relapse/progression samples). Genomic profiling of matched tumor samples revealed that mutations present in primary tumors are generally maintained in the relapse/disease progression. We did not find a significant increase in point mutations between primary and relapse/progression samples, although gene amplifications were found more frequently in relapse/progression samples. Tumor samples harbored high frequency of TP53 (100%) and TERT promoter (29%) mutations, and of MYC amplifications (80% of which in relapse/progression samples). No PI3KCA mutations were found, but PTEN variations were enriched in 38% of samples (10% mutations and 28% deletions). FGFR1 amplifications were identified in 13% of samples (primary tumor only). Neither ERBB2 nor EGFR gene amplifications were detected. The most frequent pathogenic alterations occurred in cycle regulation's genes, including TP53 and TERT promoter mutations, and MYC amplifications. Relapse/progression samples were highly enriched for MYC amplification. Larger studies are required to better characterize these tumors, and identify new strategies to improve the prognosis of these patients., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Background: Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers., Methods: We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients., Results: Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events., Conclusions: In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: Carcinomatous meningitis (CM) is a severe complication of breast cancer. The Breast International Group (BIG) carried out a survey to describe the approach to CM internationally., Patients and Methods: A questionnaire on the management of CM was developed by the Brain Metastases Task Force of BIG and distributed to its groups, requesting one answer per group site., Results: A total of 241 sites responded, 119 from Europe, 9 from North America, 39 from Central/South America, 58 from Asia, and 16 in Australia/New Zealand, with 24.5% being general hospitals with oncology units, 44.4% university hospitals, 22.4% oncology centers, and 8.7% private hospitals. About 56.0% of sites reported seeing <5 cases annually with 60.6% reporting no increase in the number of cases of CM recently. Nearly 63.1% of sites investigate for CM when a patient has symptoms or radiological evidence, while 33.2% investigate only for symptoms. For diagnosis, 71.8% of sites required a positive cerebrospinal fluid cytology, while magnetic resonance imaging findings were sufficient in 23.7% of sites. Roughly 97.1% of sites treat CM and 51.9% also refer patients to palliative care. Intrathecal therapy is used in 41.9% of sites, mainly with methotrexate (74.3%). As many as 20 centers have a national registry for patients with breast cancer with central nervous system metastases and of those 5 have one for CM. Most (90.9%) centers would be interested in participating in a registry as well as in studies for CM, the latter preferably (62.1%) breast cancer subtype specific., Conclusions: This is the first study to map out the approach to CM from breast cancer globally. Although guidelines with level 1 evidence are lacking, there is a high degree of homogeneity in the approach to CM globally and great interest for conducting studies in this area., Competing Interests: Disclosure ER reports consulting or advisory role for AstraZeneca, Bristol-Myers Squibb, and Pfizer; research funding from Novartis, Demo Pharmaceutical, Celldex, Radius Health, Tesaro, Parexel, and AnaBIOsis Pharmaceuticals; travel funding from Sanofi, Ipsen, Genesis Pharmaceuticals, LEO Pharma, Merck, Roche, and GENEKOR. CP reports grant funding from Pfizer and Daiichi Sankyo; honoraria from Pfizer, Roche, Daiichi Sankyo, Novartis, Exact sciences, Gilead, Seagen, and Eli Lilly. VM reports honoraria from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, Seagen, Novartis, Roche, Teva, Janssen-Cilag, and Gilead; playing an advisory role for Hexal, Roche, Pfizer, Amgen, Daiichi-Sankyo, Nektar, Seagen, Gilead, and Eisai; research funding from Roche, Novartis, Seagen, Pfizer, and Genentech. RB reports advisory role for Astra-Zeneca, Daiichi, Eisai, Eli-Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche, and Seagen; lecture honoraria from Astra-Zeneca, Daiichi, Eli-Lilly, Novartis, Pfizer, Pierre-Fabre, Roche, and Seagen; research support from Daiichi, MSD, Novartis, and Roche. GR reports research funding (institution) from AstraZeneca, Roche/Genentech, Tesaro, Novartis, Pfizer, Servier, Biovica, GlaxoSmithKline, and Sanofi/Aventis; and patents, royalties, other intellectual property from Agendia for MammaPrint due to the collaboration on the conduct of the MINDACT trial (Institution). SPG reports honoraria from Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, and Seagen; advisory/consultancy roles with Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, and Seagen; research grant from Roche; travel/accommodation/expenses from Roche, Amgen, Shire, Novartis, Pfizer, Bayer, Celgene, and Daiichi Sankyo. HCK reports honoraria and travel support from AstraZeneca, Pfizer, Roche, Daiichi Sankyo, Tesaro, MSD, Onkowissen, Eli Lilly, SurgVision, Exact Sciences, and Genomic Health; and Stock ownership from Theraclion and Phaon scientific. NZ is on the advisory board for Lilly, Eisai, and AstraZeneca; reports receiving honorarium from Roche, Pfizer, Eisai, and Amgen; research funding (institutional) from Pfizer, Roche, and GSK; education funding from Roche, Novartis, and Amgen (none considered relevant to the current work). MP is on the advisory boards, and has participated in educational programs and conferences for Pfizer, BMS, Novartis, Astellas, Janssen, MD Serono, Merck, Amgen, and Sanofi; reports research funding (institutional) from Astellas, Novartis, Roche, Merck, BMS, Sanofi, and AstraZeneca. RMC has received (to institution) an unrestricted educational grant from Pfizer; and research funds from MSD Ireland and Pfizer. HT reports employment or management position with Partner and Medical Director Oncology Practice at Bethanien Hospital, Frankfurt; honoraria from Novartis, Roche, GSK, Seagen, Pfizer, Lilly, AstraZeneca, Daiichi, and Exact Science; consulting activities for Novartis, Roche, GSK, Seagen, Pfizer, Lilly, AstraZeneca, Daiichi, and Exact Science. AM reports advisory/consultant role, honoraria, and research grant from Lilly and Roche; advisory/consultant role for Novartis, Merck, Seagen, and Daiichi-Sankyo. LDM reports grants from Eli Lilly during the conduct of the study; personal fees from Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, AstraZeneca, Seagen, Ipsen, and Gilead; personal fees and nonfinancial support from Roche, Pfizer, and Eisai, outside the submitted work. CC reports honoraria from Amgen, AstraZeneca, BMS, Genesis, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche. SO reports lecture fees, honoraria, or other fees paid by a single company or for-profit organization for the time or labor of a researcher engaged for conference attendance from Chugai, Lilly, AstraZeneca, and Pfizer. IM reports performing consultancy roles for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, In3Bio, MSD, Novartis, Pfizer, and Roche; travel/conference registration activities for Eli Lilly, Daiichi Sankyo, Gilead, and Novartis. ME serves on the advisory boards of Pfizer and Novartis; lecturing for Astra Zeneca (institution), but has no conflicts of interest related to this publication. KZ serves on the advisory board or performs talk for AstraZeneca, Daiichi, Exact Sciences, Lilly, Pierre Fabre, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Viatris/Mylan; unrestricted funding for organization of academic symposium from Agendia, AstraZeneca-MSD, Daiichi, Eisai, Exact Sciences, Lilly, Pierre Fabre, Gilead, Novartis, Pfizer, Roche, Seagen, Viatris/Mylan, and Vifor; support for participation in international congress from AstraZeneca, Daiichi, Pierre Fabre, and Roche; is a member of steering committee of Eleanor study (Pierre Fabre); and research funding from Roche. MV reports honoraria from Roche, Novartis, Pfizer, and Daiichi; consulting or advisory role for Novartis and Roche; travel funds from Roche and Pfizer. DF’s institution receives support from F. Hoffmann-La Roche Ltd/Genentech, AstraZeneca, Novartis, Servier, Tesaro, Sanofi, and Pfizer for the conduct of clinical trials outside the submitted work. MG-G reports honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Novartis, and Pierre Fabre; travel/attending meetings for Pfizer, Roche, and Novartis; participation on a Data Safety Monitoring Board or Advisory Board for Daiichi Sankyo and AstraZeneca. BL reports consulting or advisory role for AstraZeneca, Pfizer, Merck, Eli Lilly, Pierre Fabre, and Daiichi Sankyo. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: An earlier analysis of the PEARL phase III study showed that palbociclib plus endocrine therapy (ET) does not improve progression-free survival (PFS) over capecitabine in aromatase inhibitor-resistant, hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) patients. Here, we report the final overall survival (OS) analysis., Methods: Postmenopausal patients (N = 601) were randomized 1:1 to capecitabine or palbociclib plus ET (exemestane, Cohort 1; fulvestrant, Cohort 2). OS was analysed in Cohort 2, the wild-type ESR1 population and the overall population. Additionally, we analysed subsequent systemic therapies and explored PFS2 (time from randomization to the end of the first subsequent therapy/death)., Results: OS was 31.1 months for palbociclib plus fulvestrant and 32.8 months for capecitabine (adjusted hazard ratio [aHR] 1.10, 95% confidence interval [CI] 0.81-1.50, P = 0.550). In the wild-type ESR1 population, OS was 37.2 months for palbociclib plus ET and 34.8 months for capecitabine (aHR 1.06, 95% CI 0.81-1.37, P = 0.683). In OS analyses, no subgroup showed superiority for palbociclib plus ET over capecitabine. OS in the overall population was 32.6 months for palbociclib plus ET and 30.9 months for capecitabine (P = 0.995). Subsequent systemic therapy was given to 79.8% and 82.9% of patients with palbociclib plus ET and capecitabine, respectively. Median PFS2 was similar between study arms (Cohort 2, P = 0.941; wild-type ESR1 population, P = 0.827). No new safety findings were observed., Conclusions: Palbociclib plus ET did not show a statistically superior OS compared to capecitabine in MBC patients progressing on aromatase inhibitors., Trial Registration: NCT02028507 (ClinTrials.gov), 2013-003170-27 (EudraCT)., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Martín has received consulting fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology and Pfizer; speakers' honoraria from AstraZeneca, Amgen, Roche/Genentech, Novartis, Daiichi-Sankyo and Pfizer; contracted research fees from Roche, Novartis and PUMA. C. Zielinski has received consulting fees and speaker's honoraria from Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier, Shire, Eli Lilly and Athenex. His institution, Central European Cancer Center, Wiener Privatklinik Hospital, has received fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, AstraZeneca and Merck KGaA. M. Ruiz-Borrego has received speaker fees and advisory grants from Pfizer, Novartis and Lilly. E. Carrasco, who has a stock and other ownership interests from Lilly, has received travel and accommodation support from Roche, and her husband, who has participated in consulting and advisory board activities with Bristol-Myers Squibb, Novartis, Celgene, Roche Pharma, Janssen, Amgen, Incyte, Abbvie and Pfizer, has received travel and accommodation support from Celgene, Novartis and Bristol-Myers Squibb. His institution has received research funding from Celgene, Janssen, Bristol-Myers Squibb, Novartis, Celgene, Roche/Genentech, Amgen, Pfizer and Abbvie. GEICAM has received research funding from Roche/Genentech, Bristol-Myers Squibb, Novartis, Pfizer, Celgene, AstraZeneca, Merck Sharp & Dohme, Pierre Fabre and Takeda. E. M. Ciruelos has received advisory board honoraria from Lilly, Novartis, MSD, AstraZeneca, Pfizer and Roche; speakers' honoraria from Roche, Lilly and Pfizer; travel and congress assistance support from Pfizer and Roche. M. Muñoz has received advisory board honoraria from Pierre Favre and Seagen; honoraria for expert testimony from Novartis, Roche and Eisai; travel and congress assistance support from Roche, Novartis, Pfizer and Eisai. B. Bermejo has received advisory board honoraria from Roche, Novartis and MSD; speakers' honoraria from Roche, Novartis, MSD, Pfizer and Pierfabre; travel and congress assistance support from Pfizer. M. Margelí has received advisory board fees from Roche, Novartis, Pfizer and Eisai. Her institution, ICO-Badalona. B-ARGO (Badalona Applied Research Group in Oncology) Hospital Universitari Germans Trias i Pujol, Badalona, has received funding research from Roche, Pfizer, Novartis, Lilly, AstraZeneca, Eisai and Kern, and she has received travel and congress assistance support from Roche. A. Antón has received advisory board fees from Bayer Spain, Lilly and Gilead. N. Turner has received advisory board honoraria from Astra Zeneca, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Bicycle Therapeutics, Taiho, Zeno pharmaceuticals and Repare; therapeutics and research funding from Astra Zeneca, BioRad, Pfizer, Roche/Genentech, Clovis, Merck Sharp & Dohme and Guardant Health. E. Alba has received advisory board fees from Roche, Novartis, Pfizer, Lilly, Bristol-Myers Squibb, Genomic Health and Nanostring. He has received travel support from Celgene. His institution, Hospitales Regional y Virgen de la Victoria, Málaga, has received funding research from Roche, Pfizer, Sysmex, Merck Sharp & Dohme and Nanostring. J. de la Haba-Rodríguez has received speaker's honoraria from AstraZeneca, Pfizer, Novartis and Lilly. M. Ramos has received honoraria from Novartis, Roche and Pfizer. M. Corsaro is employed by Pfizer and has company stock options. X. Huang is employed by Pfizer and has company stock options. Z. Kahan has participated in advisory boards of and received speaker fees or travel support from Pfizer, Roche, AstraZeneca and Novartis. M. Gil-Gil has received honoraria from Pfizer, Ferrer International and Esteve Pharma. All remaining authors have declared no conflicts of interest. A complete list of the PEARL trial collaborators is provided in the Supplementary Appendix., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: MET-signaling and midkine (ALK ligand) promote glioma cell maintenance and resistance against anticancer therapies. ALK and c-MET inhibition with crizotinib have a preclinical therapeutic rationale to be tested in newly diagnosed GBM., Methods: Eligible patients received crizotinib with standard radiotherapy (RT)/temozolomide (TMZ) followed by maintenance with crizotinib. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3 + 3 dose escalation (DE) strategy and safety evaluation in the expansion cohort (EC). Secondary objectives included progression-free (PFS) and overall survival (OS) and exploratory biomarker analysis., Results: The study enrolled 38 patients. The median age was 52 years (33-76), 44% were male, 44% were MGMT methylated, and three patients had IDH1/2 mutation. In DE, DLTs were reported in 1/6 in the second cohort (250 mg/QD), declaring 250 mg/QD of crizotinib as the RP2D for the EC. In the EC, 9/25 patients (32%) presented grade ≥3 adverse events. The median follow up was 18.7 months (m) and the median PFS was 10.7 m (95% CI, 7.7-13.8), with a 6 m PFS and 12 m PFS of 71.5% and 38.8%, respectively. At the time of this analysis, 1 died without progression and 24 had progressed. The median OS was 22.6 m (95% CI, 14.1-31.1) with a 24 m OS of 44.5%. Molecular biomarkers showed no correlation with efficacy., Conclusions: The addition of crizotinib to standard RT and TMZ for newly diagnosed GBM was safe and the efficacy was encouraging, warranting prospective validation in an adequately powered, randomized controlled study.

Introduction: The Objective was to investigate the incidence of lymphedema after breast cancer treatment and to analyze the risk factors involved in a tertiary level hospital., Methods: Prospective longitudinal observational study over 3 years post-breast surgery. 232 patients undergoing surgery for breast cancer at our institution between September 2013 and February 2018. Sentinel lymph node biopsy (SLNB) or axillary lymphadenectomy (ALND) were mandatory in this cohort. In total, 201 patients met the inclusion criteria and had a median follow-up of 31 months (range, 1-54 months). Lymphedema was diagnosed by circumferential measurements and truncated cone calculations. Patients and tumor characteristics, shoulder range of motion limitation and local and systemic therapies were analyzed as possible risk factors for lymphedema., Results: Most cases of lymphedema appeared in the first 2 years. 13.9% of patients developed lymphedema: 31% after ALND and 4.6% after SLNB (p < 0.01), and 46.7% after mastectomy and 11.3% after breast-conserving surgery (p < 0.01). The lymphedema rate increased when axillary radiotherapy (RT) was added to radical surgery: 4.3% for SLNB alone, 6.7% for SLNB + RT, 17.6% for ALND alone, and 35.2% for ALND + RT (p < 0.01). In the multivariate analysis, the only risk factors associated with the development of lymphedema were ALND and mastectomy, which had hazard ratios (95% confidence intervals) of 7.28 (2.92-18.16) and 3.9 (1.60-9.49) respectively., Conclusions: The main risk factors for lymphedema were the more radical surgeries (ALND and mastectomy). The risk associated with these procedures appeared to be worsened by the addition of axillary radiotherapy. A follow-up protocol in patients with ALND lasting at least two years, in which special attention is paid to these risk factors, is necessary to guarantee a comprehensive control of lymphedema that provides early detection and treatment.

Background: The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear., Methods: In a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival., Results: A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased., Conclusions: Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.)., (Copyright © 2021 Massachusetts Medical Society.)