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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.)

Importance: The cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population., Objective: To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario., Design, Setting, and Participants: In this international, randomized, open-label, phase 2 clinical study conducted from July 30, 2015, to January 8, 2018, patients with hormone receptor-positive, ERBB2-negative advanced breast cancer with no prior therapy in the metastatic setting and endocrine-sensitive criteria were recruited from 47 centers in 7 countries. Data were analyzed from February 11 to May 15, 2020., Interventions: Patients were randomly assigned (1:1 ratio) to receive palbociclib with either fulvestrant or letrozole. Stratification factors were type of disease presentation (de novo vs recurrent) and the presence of visceral involvement (yes vs no)., Main Outcomes and Measures: The primary end point was investigator-assessed progression-free survival determined by Response Evaluation Criteria in Solid Tumors, version 1.1., Results: A total of 486 women (median age, 63 years [range, 25-90 years]; 3 Asian women [0.6%]; 4 Black women [0.8%]; 461 White women [94.9%]; 18 women of unknown race [3.7%]) were randomized (243 to fulvestrant-palbociclib and 243 to letrozole-palbociclib). Median investigator-assessed progression-free survival was 27.9 months (95% CI, 24.2-33.1 months) in the fulvestrant-palbociclib group vs 32.8 months (95% CI, 25.8-35.9 months) in the letrozole-palbociclib group (hazard ratio, 1.13; 95% CI, 0.89-1.45; P = .32). This result was consistent across the stratification factors. No significant differences were observed in objective response rate (46.5% vs 50.2%) and 3-year overall survival rate (79.4% vs 77.1%) for fulvestrant-palbociclib and letrozole-palbociclib, respectively. Grade 3-4 adverse events were comparable among treatment groups, and no new safety signals were identified. No treatment-related deaths were reported., Conclusions and Relevance: Although fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT02491983.

Background: The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes., Patients and Methods: The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively., Results: Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs. -2.1 for capecitabine (95% confidence interval [CI], 1.4-8.6; P = 0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomiting and appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale., Conclusion: Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated., Trial Registration Number: NCT02028507 (ClinTrials.gov)., Eudract Study Number: 2013-003170-27., Competing Interests: Conflict of interest statement Z.K. has participated in advisory boards of and received speaker fees or travel support from Pfizer, Roche, AstraZeneca and Novartis. M.G-G.- has received honoraria from Pfizer and Eisai and has participated in advisory boards of Genentech and Daiichi Sankyo. He has received travel support from Pfizer, Novartis, Daiichi Sankyo, Roche and Kern. M.R.B. has received speaker fees and advisory grants from Pfizer, Novartis and Lilly. E.Ca., 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, 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.Ci. has received advisory board honoraria from Lilly, Novartis, MSD, AstraZeneca, Pfizer and Roche and speakers' honoraria from Roche, Lilly and Pfizer, and she has received travel and congress assistance support from Pfizer and Roche. M.Mu. has received travel and congress assistance support from Roche, Novartis, Pfizer and Eisai. B.B. has received advisory board honoraria from Roche, Novartis and MSD and speakers' honoraria from Roche, Novartis, MSD, Pfizer and Pierre Fabre, and she has received travel and congress assistance support from Pfizer. M.Marg. 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 research funding from Roche, Pfizer, Novartis, Lilly, AstraZeneca, Eisai and Kern, and she has received travel and congress assistance support from Roche. A.A. has received advisory board fees from Bayer, Spain. E.A. 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 research funding from Roche, Pfizer, Sysmex, Merck Sharp & Dohme and Nanostring. J.d.l.H-R. has received speaker's honoraria from AstraZeneca, Pfizer, Novartis and Lilly. M.R. has received honoraria from Novartis, Roche and Pfizer. I.M.A-L. has received consulting or advisory board honoraria from AstraZeneca, Pfizer, Novartis, Palex and Roche; speakers' honoraria from AstraZeneca, Pfizer, Novartis, Roche and Eisai; travel and congress assistance support from AstraZeneca, Pfizer, Roche and Eisai and research funding from Pfizer, Novartis, AstraZeneca and Roche. E.G-Y. has received honoraria and travel support and has participated in advisory boards for Pfizer, Roche, Novartis and Eli Lilly. S.G-S. has received consulting or advisory board honoraria from Pfizer, MSD, GSK and Roche and speakers' honoraria from AstraZeneca, Pfizer and Novartis. C.A.R. has received consulting or advisory board honoraria from AstraZeneca, Pfizer, Novartis, SeaGen, DaiiChi Sankyo and Roche and speakers' honoraria from MSD, Pfizer, Novartis, Roche, Nanostring, Amgen and Eisai. S.S. has received consulting or advisory board or speakers' honoraria from Roche, Eisai, Daiichi Sankyo, AstraZeneca, MSD and Genomic Health. M.C. is employed by Pfizer and has the company's stock options. X.H. is employed by Pfizer and has the company's stock options. C.Z. 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.Mart. 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 and contracted research fees from Roche, Novartis and PUMA. All remaining authors have declared no conflicts of interest. A complete list of the PEARL trial collaborators is provided in the Supplementary Appendix., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To report the outcomes of implementing the ACOSOG Z0011 and AMAROS trials relevant to clinical practice, and to define target groups in whom to avoid or recommend axillary radiotherapy (ART). We also aimed to analyse the reduction in morbidity when axillary lymph node dissection (ALND) was omitted., Methods: A retrospective cohort study of T1-T2 patients with macrometastases at sentinel lymph node (SLN) who were treated between 2011 and 2020. Breast surgery included either lumpectomy or mastectomy. Patients with ≤ 2 positive SLN were divided into two cohorts by whether they received ART or not. Survival outcomes and morbidity were analysed by Kaplan-Meyer curves and Cox-regression, respectively., Results: 260 pN1a patients were included and ALND was avoided in 167 (64.2%). According the Z0011 results, 72 (43.1%) received no further ART; and based on AMAROS criteria 95 (56.9%) received ART. Median follow-up was 54 months. The 5-year overall survival was 96.8% in the non-RT cohort and 93.4% in the RT cohort (p = 0.19), while the respective 5-year disease-free survivals were 100% and 92.3% (p = 1.06). Lymphedema developed in 3.6% of patients after SLNB versus 43% after ALND (OR 20.25; 95%CI 8.13-50.43). Decreased upper-extremity range of motion appeared in 8.4% of patients after SLNB versus 31.2% after ALND (OR 4.95; 95%CI 2.45-9.98%)., Conclusions: Our study confirms that omitting ALND is safe and has high survival rates in patients with T1-T2 tumours and ≤ 2 positive SLNs. Adding ART could be a treatment option for patients who present other risk factors. Avoiding ALND with or without ART was associated with significantly less arm morbidity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has proven to be a successful strategy in the treatment of advanced hormone receptor-positive (HR + ) and human epidermal growth factor receptor 2-negative (HER2 - ) breast cancer (BC), leading to a strong interest in their possible role in the treatment of early luminal BC. In this review we collect the most relevant and recent information on the use of CDK4/6i for the treatment of early BC in the neoadjuvant and adjuvant settings. Specifically, we evaluate the results of the large phase 3 adjuvant trials recently released, which have yielded apparently divergent results. We also examine the relevance of biomarkers as response predictive factors for CDI4/6i, the combination between radiotherapy and CDK4/6i, and provide a critical discussion on the evidence that we have so far and future directions of the role of these drugs in the treatment of early BC., Competing Interests: Declaration of competing interest MGG reports consulting fees and honoraria from Pfizer, Agendia, and Kern; advisory roles for AstraZeneca and Daiichi-Sankyo; travel grants from Pfizer, Roche, Novartis, and Kern. EA reports advisory roles for Roche, Novartis, Pfizer, Eli Lilly, BMS, AstraZeneca, Genomic Health, and Nanostring; travel grants from Celgene; research grants from Roche, Pfizer, Sysmex, MSD, and Nanostring. JG reports consulting fees and honoraria from Novartis, Pfizer, AstraZeneca and Daiichi-Sankyo; advisory roles for Novartis, Pfizer, Eli Lilly and AstraZeneca. JdlH-R reports consulting fees and honoraria from Pfizer, Novartis, and Agendia; advisory roles for AstraZeneca, Daiichi-Sankyo, Pfizer, Novartis and Roche; travel grants from Astra Zeneca, Pfizer, Roche and Novartis. EC reports consulting fees from Pfizer, Eli Lilly, Roche, Novartis, AstraZeneca and MSD; participating as a speaker for Roche, Pfizer and Eli Lilly; travel grants from Roche and Pfizer. PT reports personal fees from AstraZeneca and honoraria for participation in advisory boards from Amgen, AstraZeneca, MSD, Roche, Pfizer and Eisai. DC is an employee of and may own stock in Pfizer Inc. AL-C reports owing stock, patents and intellectual property with MedSIR; consultant for AstraZeneca, Daiichi-Sanyo, MSD, Novartis, Pfizer, Roche and Eli Lilly; research funding from Eisai, Daiichi-Sanyo, Roche, Pfizer, Eli Lilly, MSD, Genomic-Health, Agendia and Pierre Fabre; travel grants from Roche, Pfizer and Eli Lilly; providing expert testimony for AstraZeneca., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial., Patients and Methods: PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA., Results: From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85)., Conclusions: There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life., Competing Interests: Disclosure MM 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. CZ 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. MRB has received speaker fees and advisory grants from Pfizer, Novartis, and Lilly. EC, 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. NT has received advisory board honoraria from AstraZeneca, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Bicycle Therapeutics, Taiho, Zeno Pharmaceuticals, and Repare Therapeutics and research funding from AstraZeneca, Bio-Rad, Pfizer, Roche/Genentech, Clovis, Merck Sharp & Dohme, and Guardant Health. MM has received travel and congress assistance support from Roche, Novartis, Pfizer, and Eisai. BB has received advisory board honoraria from Genentech, Novartis, Merck Sharpe and Dohme, speakers’ honoraria from Genentech, Eisai and she has received travel and congress assistance support from Pfizer. MM has received advisory board fees from Roche, Novartis, Pfizer, and Eisai. Her institution, Hospital Universitari Germans Trias i Pujol, Badalona, has received funding research from Roche, Pfizer, Novartis, Lilly, AstraZeneca, Eisai, and Kern. AA has received advisory board fees from Bayer, Spain. EA 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. EG-Y has received honoraria, travel support, and has participated in advisory boards for Pfizer, Roche, Novartis, and Eli Lilly. ÁG-Z has received investigational fees and travel support from Pfizer. JdelaH has received honoraria from AstrazZeneca, Pfizer, Novartis, Roche, and Agendia. MR has received honoraria from Novartis, Roche, and Pfizer. IÁ has received consulting or advisory board honoraria from AstraZeneca, Pfizer, Novartis, and Roche; speakers’ honoraria from AstraZeneca, Pfizer, Novartis, Roche, and Eisai; travel and congress assistance support from AstraZeneca, Pfizer, Roche, and Eisai. CH has a stock from Pfizer and AstraZeneca, she was an employee of Pfizer during the study, and is an employee of AstraZeneca currently, where she holds a stock. MK has Pfizer stock and was an employee of Pfizer during the study. MC is employed by Pfizer and has the company’s stock options. XH is employed by Pfizer and has the company’s stock options. JAG-S has consultancy/speaker fees from Novartis, Celgene, Eli Lilly, Eisai, and AstraZeneca. He received travel support from Novartis, Roche, and Pfizer. His institution, Hospital Clínico Universitario San Carlos, received research funding from AstraZeneca. MG-G has received honoraria from Pfizer and Eisai and has participated in advisory boards of Genentech and Daiichi-Sankyo. He has received travel support from Pfizer, Novartis, Daiichi-Sankyo, Roche, and Kern. All remaining authors have declared no conflicts of interest. A complete list of the PEARL trial collaborators is provided in the Supplementary Appendix., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To find a group of cN2 patients or patients with high axillary burden who become ypN0 after neoadjuvant chemotherapy (NACT) and who may benefit from avoiding a lymphadenectomy., Methods: A retrospective observational cohort study was conducted with 221 clinically staged N2 patients or patients with at least 3 suspicious lymph nodes found by ultrasound at diagnosis. The predictive factors for ypN0 analysed were age, MRI-determined tumour size, histological subtype, the Nottingham histologic grade, surrogate molecular subtype, ki-67 and vascular invasion when present. Clinical and radiological responses after NACT were also evaluated. Univariate and multivariate analyses by logistic regression were performed. Distant disease-free survival (DDFS) was calculated in relation to the status of the axillary lymph nodes after NACT., Results: After NACT, 89 patients (40.3%) had axillary pathologic complete response (pCR) (ypN0) and 132 (59.7%) had residual axillary disease (ypN+). Molecular surrogate subtype, Ki-67 expression, and the clinical and radiological responses to NACT were the only independent factors associated with ypN0. Axillary pCR was observed more often in HER2-positive and triple-negative tumours than in luminal ones (OR 7.5 and 3.6, respectively). DDFS was 88.7% (95% CI 80.7-96.7%) for ypN0 and 56.2% (95% CI 32.1-80.3%) for ypN+ (p = 0.09)., Conclusions: In HER2-positive and triple-negative breast cancer patients staged as cN2 or with high axillary burden before NACT, a sentinel lymph node biopsy after NACT could be recommended if there is a clinical and radiological response.

Purpose: Glioblastoma is the most aggressive brain tumor in adults and has few therapeutic options. The study of molecular subtype classifications may lead to improved prognostic classification and identification of new therapeutic targets. The Cancer Genome Atlas (TCGA) subtype classification has mainly been applied in U.S. clinical trials, while the intrinsic glioma subtype (IGS) has mainly been applied in European trials., Experimental Design: From paraffin-embedded tumor samples of 432 patients with uniformly treated, newly diagnosed glioblastoma, we built tissue microarrays for IHC analysis and applied RNA sequencing to the best samples to classify them according to TCGA and IGS subtypes., Results: We obtained transcriptomic results from 124 patients. There was a lack of agreement among the three TCGA classificatory algorithms employed, which was not solely attributable to intratumoral heterogeneity. There was overlapping of TCGA mesenchymal subtype with IGS cluster 23 and of TCGA classical subtype with IGS cluster 18. Molecular subtypes were not associated with prognosis, but levels of expression of 13 novel genes were identified as independent prognostic markers in glioma-CpG island methylator phenotype-negative patients, independently of clinical factors and MGMT methylation. These findings were validated in at least one external database. Three of the 13 genes were selected for IHC validation. In particular, high ZNF7 RNA expression and low ZNF7 protein expression were strongly associated with longer survival, independently of molecular subtypes., Conclusions: TCGA and IGS molecular classifications of glioblastoma have no higher prognostic value than individual genes and should be refined before being applied to clinical trials., (©2020 American Association for Cancer Research.)

The objective of this observational study was to evaluate the efficacy and safety of duloxetine in a cohort of 100 cancer survivors with chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN was graded employing the TNSc and the NCI-CTCv4. The Patient Global Impression of Change (PGIC) scale measured the efficacy of duloxetine (1: no benefit; to 7: excellent response). A clinically meaningful response was considered a PGIC > 4. Median age was 62 (29-81) years and 42% were male. CIPN was graded as grades 1, 2 and 3 in 20, 66, and 14% of patients, respectively. Median time to duloxetine initiation was 6 (1-63) months after chemotherapy. Fifty-seven patients early dropped out from duloxetine, due to lack of efficacy (20%) or side effects (37%). Male patients more frequently discontinued duloxetine due to lack of efficacy (35.7 vs. 8.6% P = 0.001). PGIC scores were higher in female patients (4 vs. 1, P = 0.001), taxane-treated patients (4 vs. 1, P = 0.042) and with short-lasting (<6 months) CIPN (4 vs. 1, P = 0.008). Patients with long-lasting CIPN had a higher rate of adverse events (47 vs. 27%, P = 0.038) and discontinuation (54.8 vs. 45.1%, P = 0.023). In the multivariate analysis, female gender and short-lasting CIPN were independently associated with a favorable response to duloxetine. Low tolerability, male gender, and long-lasting CIPN significantly limited duloxetine use in daily practice setting. A minority of cancer survivors with CIPN treated with duloxetine had a meaningful CIPN improvement, and tolerability was overall low. Female gender and short-term CIPN were independently associated with a favorable response to duloxetine., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Standard treatment for glioblastoma is radiation with concomitant and adjuvant temozolomide for 6 cycles, although the optimal number of cycles of adjuvant temozolomide has long been a subject of debate. We performed a phase II randomized trial investigating whether extending adjuvant temozolomide for more than 6 cycles improved outcome., Methods: Glioblastoma patients treated at 20 Spanish hospitals who had not progressed after 6 cycles of adjuvant temozolomide were centrally randomized to stop (control arm) or continue (experimental arm) temozolomide up to a total of 12 cycles at the same doses they were receiving in cycle 6. Patients were stratified by MGMT methylation and measurable disease. The primary endpoint was differences in 6-month progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and safety (Clinicaltrials.gov NCT02209948)., Results: From August 2014 to November 2018, 166 patients were screened, 7 of whom were ineligible. Seventy-nine patients were included in the stop arm and 80 in the experimental arm. All patients were included in the analyses of outcomes and of safety. There were no differences in 6-month PFS (control 55.7%; experimental 61.3%), PFS, or OS between arms. MGMT methylation and absence of measurable disease were independent factors of better outcome. Patients in the experimental arm had more lymphopenia (P < 0.001), thrombocytopenia (P < 0.001), and nausea and vomiting (P = 0.001)., Conclusions: Continuing temozolomide after 6 adjuvant cycles is associated with greater toxicity but confers no additional benefit in 6-month PFS., Key Points: 1. Extending adjuvant temozolomide to 12 cycles did not improve 6-month PFS.2. Extending adjuvant temozolomide did not improve PFS or OS in any patient subset.3. Extending adjuvant temozolomide was linked to increased toxicities., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lessons Learned: The levels of circulating follicle-stimulating hormone, luteinizing hormone, estriol, estradiol, and estrone remained unchanged after a 12-week treatment with 0.005% estriol vaginal gel in postmenopausal women receiving nonsteroidal aromatase inhibitors for hormone receptor-positive early breast cancer. These results support the safety of 0.005% estriol vaginal gel for the treatment of bothering symptoms of vulvovaginal atrophy in breast cancer survivors. The results provide clinicians with confidence in the use of this product in women who do not experience symptom relief with nonhormonal remedies., Background: Symptoms of vulvovaginal atrophy associated with treatment with nonsteroidal aromatase inhibitors (NSAIs) negatively impact patients' quality of life and may affect adherence to NSAIs. Vaginal estrogens effectively improve these symptoms, although their safe use in breast cancer survivors remains unclear., Methods: Postmenopausal women with hormone receptor-positive early breast cancer receiving NSAI and moderate-to-severe vaginal dryness were randomized to 0.005% estriol vaginal gel or placebo for 12 weeks. Circulating estrogens, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), were analyzed at baseline and at weeks 1, 3, 8, and 12. The primary safety outcome was the variation in serum FSH from baseline to week 12., Results: Sixty-one women (mean age, 59 years) enrolled in the study. Small oscillations were observed in FSH and LH, although they were always maintained within the postmenopausal range. No significant differences were found in the variation of FSH and LH between baseline and week 12 from the physiological variation observed before treatment. Women receiving 0.005% estriol vaginal gel had slightly increased estriol levels at weeks 1 and 3, with a subsequent reduction until normalizing at week 12; estradiol and estrone remained the below limit-of-quantitation in almost all samples., Conclusion: Ultralow-dose 0.005% estriol vaginal gel did not significantly influence estrogens, FSH, and LH levels in women with breast cancer receiving NSAI. A transient negligible absorption of estriol and a nonsignificant variation of FSH after 12 weeks were observed. These findings provide confidence for the safe use of 0.005% estriol vaginal gel in women with breast cancer with an indication for treatment with vaginal estrogens., (© 2020 ITF Research Pharma S.L.U. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Metastatic breast cancer (MBC) diagnosis in young women negatively impacts on quality of life (QoL) and daily activities, disrupting their life project and forcing them to face new psychosocial challenges. The recently published results on the improvement of the overall survival of pre- or perimenopausal women with hormone-receptor-positive, HER2-negative MBC treated with CDK4/6 inhibitors plus endocrine therapy, while preserving, and in some items improving their QoL, will change the landscape of the management of this patient population. Their extended survival and potential improvement in QoL will, therefore, modify their specific needs in terms of psychosocial support. The complexity of the care of young women with MBC is described herein, based on an extensive literature review. Further research about the specific psychosocial requirements of these women and a new multidisciplinary holistic approach is paramount to properly address their concerns and preferences. The communication with and support of their partners, parents and children is an important factor affecting the QoL of these patients. Altogether, a multidisciplinary care, open communication and personalized support is required to address the psychosocial implications of the new prognostic expectations on these patients with the incorporation of new targeted therapies., Competing Interests: Declaration of competing interest Mireia Margelí Vila has received honoraria from Novartis, Pfizer, Pierre Fabre and Roche. Sonia del Barco Berron has received honoraria from Novartis. Miguel Gil-Gil has received honoraria from Daiichi, Eisai, Genentech, Novartis and Pfizer and reimbursement of congress travel expenses from Roche, Daiichi and Pfizer. Cristian Ochoa-Arnedo has received honoraria from Eisai and Novartis. Rafael Villanueva Vázquez has received honoraria from Novartis, Pfizer, Eisai and Roche., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The cell cycle checkpoint G1/S, dependent on cyclin-dependent kinase (CDK) 4 amplification/overexpression and retinoblastoma phosphorylation, is altered in most anaplastic oligodendrogliomas (AOs)., Objective: We aimed to evaluate the efficacy of palbociclib, an oral inhibitor of CDK4/6 with proven efficacy in breast cancer, in patients with AO. The primary endpoint was progression-free survival at 6 months., Patients and Methods: We conducted a multicenter, open-label, phase II trial evaluating the efficacy and safety of palbociclib in patients with AO who progressed on radiotherapy and chemotherapy with histologically and molecularly confirmed grade 3 oligodendroglioma and conserved retinoblastoma protein (pRb) expression by immunohistochemistry. Patients were treated with palbociclib (125 mg/day) for 3/1 weeks on/off., Results: Overall, 34 patients were enrolled across 10 hospitals in the Spanish Group of Neuro-Oncology (GEINO) study. The study was stopped early owing to the lack of efficacy, with 74% of evaluable patients progressing within 6 months, which was insufficient to consider palbociclib as an active drug in this population. Within the median follow-up of 12 months, the median progression-free survival was 2.8 months [95% confidence interval (CI) 2.6-3.1] and the median overall survival was 32.1 months (95% CI 5.1-59.2). There were no partial or complete responses; only 13 patients (38%) achieved stable disease as the best response. Palbociclib was well tolerated, with neutropenia (grade 3 or higher: 58.8%) and thrombocytopenia (grade 3 or higher: 14.7%) as the most common adverse events (AEs). Both AEs had no significant impact., Conclusion: Despite the good tolerance, palbociclib monotherapy did not show favorable efficacy against recurrent AO., Trial Registration: This study is registered with ClinicalTrials.gov, identifier NCT0253032 (retrospectively registered on 21 August 2015).

Purpose: Hormone receptor (HR)-positive, Human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) requires a therapeutic approach that takes into account multiple factors, with treatment being based on anti-estrogen hormone therapy (HT). As consensus documents are valuable tools that assist in the decision-making process for establishing clinical strategies and optimize the delivery of health services, this consensus document has been created with the aim of developing recommendations on cretiera for hormone sensitivity and resistance in HER2-negative luminal MBC and facilitating clinical decision-making., Methods: This consensus document was generated using a modification of the RAND/UCLA methodology, which included the definition of the project and identification of issues of interest, a non-exhaustive systematic review of the literature, an analysis and synthesis of the scientific evidence, preparation of recommendations, and external evaluation with a panel of 64 medical oncologists specializing in breast cancer., Results: A Spanish panel of experts reached consensus on 32 of the 32 recommendations/conclusions presented in the first round and were accepted with an approval rate of 100% about definition of metastatic disease not susceptible to local curative treatment, definition of hormone sensitivity and hormone resistance in metastatic luminal disease and therapeutic decision-making., Conclusion: We have developed a consensus document with recommendations on the treatment of patients with HER2-negative luminal MBC that will help to improve therapeutic benefits.

Proper immune system function hinders cancer development, but little is known about whether genetic variants linked to cancer risk alter immune cells. Here, we report 57 cancer risk loci associated with differences in immune and/or stromal cell contents in the corresponding tissue. Predicted target genes show expression and regulatory associations with immune features. Polygenic risk scores also reveal associations with immune and/or stromal cell contents, and breast cancer scores show consistent results in normal and tumor tissue. SH2B3 links peripheral alterations of several immune cell types to the risk of this malignancy. Pleiotropic SH2B3 variants are associated with breast cancer risk in BRCA1/2 mutation carriers. A retrospective case-cohort study indicates a positive association between blood counts of basophils, leukocytes, and monocytes and age at breast cancer diagnosis. These findings broaden our knowledge of the role of the immune system in cancer and highlight promising prevention strategies for individuals at high risk., Competing Interests: Declaration of Interests M.A.P. is recipient of an unrestricted research grant from Roche Pharma for the development of the ProCURE ICO research program. C.F. received support from Pfizer unrelated to this study., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study evaluates the impact of breast cancer (BC) in health related quality of life (HRQL) and in psychological distress (PD) during the initial phases of the disease and looks for contributing factors. A multicentric case-control study, EpiGEICAM, was carried out. Incident BC cases and age- and residence- matched controls were included. Clinical, epidemiological, HRQL (SF-36) and PD information (GHQ-28) was collected. We used multivariable logistic regression models to estimate OR of low HRQL and of PD in cases compared to controls, and to identify factors associated with low HRQL and with PD. Among 896 BC cases and 890 control women, cases had poorer scores than both, the reference population and the control group, in all SF-36 scales. BC women with lower education, younger, active workers, never smokers, those with comorbidities, in stage IV and with surgical treatment had lower physical HRQL; factors associated with low mental HRQL were dissatisfaction with social support, being current smoker and having children. Cases had a fivefold increased odds of PD compared to controls. Managing comorbidities and trying to promote social support, especially in younger and less educated women, could improve well-being of BC patients.

Objective: To assess the efficacy and safety of ultra-low dose 0.005% estriol vaginal gel in women with breast cancer receiving nonsteroidal aromatase inhibitors (NSAIs) and experiencing treatment-related vulvovaginal symptoms and signs., Methods: Women with hormone receptor-positive early breast cancer receiving NSAIs were randomized to either estriol vaginal gel or placebo for 12 weeks. Vaginal maturation, vaginal pH, and total and individual scores of symptoms and signs of vulvovaginal atrophy were assessed at baseline and at weeks 3 and 12; sexual functioning was also evaluated using the Female Sexual Functioning Index (FSFI) questionnaire, as well as circulating estrogens, follicle-stimulating hormone (FSH) and luteinizing hormone (LH)., Results: Sixty-one women with a mean age of 59 years were included: 50 received 0.005% estriol vaginal gel and 11 received placebo. Active treatment significantly improved maturation value and pH, vaginal dryness and global scores of symptoms and signs. Active treatment also increased the total FSFI score and all the FSFI domains, with the exception of pain. Small oscillations were observed in FSH and LH, which remained within the postmenopausal range. Estriol levels increased initially and normalized by week 12, and estradiol and estrone remained mostly undetectable throughout the study., Conclusions: Ultra-low dose 0.005% estriol vaginal gel showed efficacy in improving the symptoms and signs of vulvovaginal atrophy. These results, together with minimal oscillations in hormonal levels throughout the treatment, support the use of ultra-low dose 0.005% estriol vaginal gel as a treatment option for vulvovaginal atrophy in women with breast cancer receiving NSAIs with an indication for treatment with vaginal estrogens. : Video Summary:http://links.lww.com/MENO/A531.

Purpose: MINDACT demonstrated that 46% of patients with early breast cancer at high clinical but low genomic risk on the basis of MammaPrint may safely avoid adjuvant chemotherapy. A second random assignment (R-C) compared docetaxel-capecitabine with an anthracycline-based regimen., Patients and Methods: R-C randomly assigned patients 1:1 between standard anthracycline-based regimens, with or without taxanes (control) and experimental docetaxel 75 mg/m 2 intravenously plus oral capecitabine 825 mg/m 2 two times per day for 14 days (DC) every 3 weeks for 6 cycles. The primary end point was disease-free survival (DFS). Secondary end points included overall survival and safety., Results: Of 2,832 patients, 1,301 (45%) were randomly assigned, and 97% complied with R-C assignment. In the control arm, 29.6% only received taxanes (0.5% of N0 patients). DFS events (n = 148) were much less than required (n = 422) as a result of a lower-than-expected accrual and event rate. At 5 years of median follow-up, DFS was not different between DC (n = 652) and control (n = 649; 90.7% [95% CI, 88% to 92.8%] v 88.8% [95% CI, 85.9% to 91.1%]; hazard ratio [HR], 0.83 [95% CI, 0.60 to 1.15]; P = .26). Overall survival (HR, 0.91 [95% CI, 0.54 to 1.53]) and DFS in the clinical high and genomic high-risk subgroup (86.1% v 88.1%; HR, 0.83 [95% CI, 0.58 to 1.21]) were similar in both arms. DC led to more grade 1 neuropathy (27.1% v 11.2%) and more grade 2 hand/foot syndrome (28.5% v 3.3%) and diarrhea (13.7% v 5.8%). Serious cardiac events occurred in 9 patients (control, n = 4; DC, n = 5). Fifty-three patients developed second cancers (control, n = 32; DC, n = 21; leukemia: 2 v 1). Five treatment-related deaths occurred (control, 2 [0.3%]; DC, 3 [0.5%])., Conclusion: Although underpowered, this second randomization in MINDACT did not show any improvement in outcome or safety with the use of DC compared with anthracycline-based chemotherapy.

Background: In hormone receptor-positive, HER2-negative early stage breast cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in combination with endocrine therapy could represent an alternative to multiagent chemotherapy. We aimed to evaluate the biological and clinical activity of neoadjuvant ribociclib plus letrozole in the luminal B subtype of early stage breast cancer., Methods: CORALLEEN is a parallel-arm, multicentre, randomised, open-label, phase 2 trial completed across 21 hospitals in Spain. We recruited postmenopausal women (≥18 years) with stage I-IIIA hormone receptor-positive, Eastern Cooperative Oncology Group Performance Status 0-1, HER2-negative breast cancer and luminal B by PAM50 with histologically confirmed, operable primary tumour size of at least 2 cm in diameter as measured by MRI. Patients were randomly assigned (1:1) using a web-based system and permuted blocks of 25 to receive either six 28-days cycles of ribociclib (oral 600 mg once daily for 3 weeks on, 1 week off) plus daily letrozole (oral 2·5 mg/day) or four cycles of doxorubicin (intravenous 60 mg/m 2 ) and cyclophosphamide (intravenous 600 mg/m 2 ) every 21 days followed by weekly paclitaxel (intravenous 80 mg/m 2 ) for 12 weeks. The total duration of the neoadjuvant therapy was 24 weeks. Randomisation was stratified by tumour size and nodal involvement. Samples were prospectively collected at baseline (day 0), day 15, and surgery. The primary endpoint was to evaluate the proportion of patients with PAM50 low-risk-of-relapse (ROR) disease at surgery in the modified intention-to-treat population including all randomly assigned patients who received study drug and had a baseline and at least one post-baseline measurement of ROR score. The PAM50 ROR risk class integrated gene expression data, tumour size, and nodal status to define prognosis. This trial was registered at ClinicalTrials.gov, NCT03248427., Findings: Between July 27, 2017 to Dec 7, 2018, 106 patients were enrolled. At baseline, of the 106 patients, 92 (87%) patients had high ROR disease (44 [85%] of 52 in the ribociclib and letrozole group and 48 [89%] of 54 in the chemotherapy group) and 14 (13%) patients had intermediate-ROR disease (eight [15%] and six [11%]). Median follow-up was 200·0 days (IQR 191·2-206·0). At surgery, 23 (46·9%; 95% CI 32·5-61·7) of 49 patients in the ribociclib plus letrozole group and 24 (46·1%; 32·9-61·5) of 52 patients in the chemotherapy group were low-ROR. The most common grade 3-4 adverse events in the ribociclib plus letrozole group were neutropenia (22 [43%] of 51 patients) and elevated alanine aminotransferase concentrations (ten [20%]). The most common grade 3-4 adverse events in the chemotherapy group were neutropenia (31 [60%] of 52 patients) and febrile neutropenia (seven [13%]). No deaths were observed during the study in either group., Interpretation: Our results suggest that some patients with high-risk, early stage, hormone receptor-positive, HER2-negative breast cancer could achieve molecular downstaging of their disease with CDK4/6 inhibitor and endocrine therapy., Funding: Novartis, Nanostring, Breast Cancer Research Foundation-AACR Career Development Award., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Eribulin improves survival in pre-treated HER2-negative advanced breast cancer (ABC). However, limited data exist on co-morbidities and central nervous system (CNS) efficacy. The purpose of this study was to review eribulin's efficacy and safety in everyday clinical practice with special focus on age, body mass index (BMI) and central nervous system (CNS) activity., Methods: An observational study was conducted in a series of HER2-negative ABC patients treated from January'14-December'17 outside a clinical trial. Objective Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS), and association of clinical and pathological variables with outcome were evaluated., Results: Ninety-five women were treated with at least one cycle of eribulin. Median age was 57 (33-83), and 18% were obese. Median number of prior chemotherapies for ABC was 3 (2-5) and 76% of patients had visceral metastases, including 21% with CNS involvement. Most tumors were estrogen receptor-positive (79%). ORR and stable disease (SD) at 6 months were 26.2 and 37.5%, respectively. Remarkably, relevant CNS efficacy was observed with eribulin: 20% of patients obtained partial response and 25% SD. Treatment was generally well tolerated and manageable, with 29% grade 3 and 10.9% grade 4 toxicities. Median PFS and OS were 4.1 months (CI95% 3.2-4.9) and 11.1 months (CI95% 9.5-14.7), respectively. Triple-negative disease, > 2organs involved and being younger than 70 years old were independent prognosis factors for worse OS in multivariate analysis. Most patients (75%) progressed in pre-existing metastases sites., Conclusion: In everyday clinical practice, eribulin's efficacy seems similar to pivotal trials. CNS-efficacy was observed. TNBC, > 2 organs involved and being younger than 70 years old were independent prognosis factors for worse OS. Remarkably, less incidence of grade 4-toxicity compared to previous studies was found.

Background: We identify cognitive impairment and MRI structural brain changes in long-term oligodendroglial tumor survivors treated with radiation therapy (RT) alone (21%) or with chemotherapy (CT) (79%)., Methods: Oligodendroglial tumor patients (based on the World Health Organization [WHO] 2007 classification) who completed RT ± CT at least 2 years before the study initiation, were classified into 3 groups according to the time treatment was completed: Group 1 = 2-5 years (n = 22), Group 2 = 6-10 years (n = 13), and Group 3 >10 years (n = 13). All patients had a cross-sectional neuropsychological evaluation (n = 48) and a longitudinal volumetric analysis (gray matter [GM; n = 34]) between postsurgical and last follow-up MRI. White matter (WM) changes on MRI were assessed using a qualitative scale., Results: There were no differences regarding tumor or treatment-related characteristics between groups. Six of 22 patients (27.3%) in Group 1; 5/13 (38.5%) in Group 2; and 9/13 (69.2%) in Group 3 had cognitive impairment that was considered severe in 3/22 patients (13.6%) in Group 1; 4/13 (30.8%) in Group 2; and 6/13 (46.2%) in Group 3. Patients in Groups 2 and 3 showed significant GM atrophy and more leukoencephalopathy than Group 1. Cognitive deficits were associated with brain atrophy and WM changes., Conclusions: Long-term oligodendroglial tumor survivors who underwent standard RT ± CT treatment, mainly >5 years of its completion, present cognitive impairment, especially on memory and executive functions, associated with late GM and WM damage, thus highlighting the need of developing future strategies in patients with oligodendroglial tumor and long expected survival., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: HER2-enriched subtype has been associated with higher response to neoadjuvant anti-HER2-based therapy across various clinical trials. However, limited data exist in real-world practice and regarding residual disease. Here, we evaluate the association of HER2-enriched with pathological response (pCR) and gene expression changes in pre- and post-treatment paired samples in HER2-positive breast cancer patients treated outside of a clinical trial. Methods: We evaluated clinical-pathological data from a consecutive series of 150 patients with stage II-IIIC HER2-positive breast cancer treated from August 2004 to December 2012 with trastuzumab-based neoadjuvant chemotherapy. Expression of 105 breast cancer-related genes, including the PAM50 genes, was determined in available pre-and post-treatment formalin-fixed paraffin-embedded tumor samples using the nCounter platform. Intrinsic molecular subtypes were determined using the research-based PAM50 predictor. Association of genomic variables with total pCR was performed. Results: The pCR rate was 53.3%, with higher pCR among hormonal receptor (HR)-negative tumors (70 vs. 39%; P < 0.001). A total of 89 baseline and 28 residual tumors were profiled, including pre- and post-treatment paired samples from 26 patients not achieving a pCR. HER2-enriched was the predominant baseline subtype not only in the overall and HR-negative cohorts (64 and 75%, respectively), but also in the HR-positive cohort (55%). HER2-enriched was associated with higher pCR rates compared to non-HER2-enriched subtypes (65 vs. 31%; OR = 4.07, 95% CI 1.65-10.61, P < 0.002) and this association was independent of HR status. In pre- and post-treatment paired samples from patients not achieving a pCR, a lower proportion of HER2-enriched and twice the number of luminal tumors were observed at baseline, and luminal A was the most frequent subtype in residual tumors. Interestingly, most (81.8%) HER2-enriched tumors changed to non-HER2-enriched, whereas most luminal A samples maintained the same subtype in residual tumors. Conclusions: Outside of a clinical trial, PAM50 HER2-enriched subtype predicts pCR beyond HR status following trastuzumab-based chemotherapy in HER2-positive disease. The clinical value of intrinsic molecular subtype in residual disease warrants further investigation.

Background: This hypothesis-generating trial evaluated neoadjuvant ipatasertib-paclitaxel for early triple-negative breast cancer (TNBC)., Patients and Methods: In this randomized phase II trial, patients with early TNBC (T ≥ 1.5 cm, N0-2) were randomized 1 : 1 to receive weekly paclitaxel 80 mg/m2 with ipatasertib 400 mg or placebo (days 1-21 every 28 days) for 12 weeks before surgery. Co-primary end points were pathologic complete response (pCR) rate (ypT0/TisN0) in the intention-to-treat (ITT) and immunohistochemistry phosphatase and tensin homolog (PTEN)-low populations. Secondary end points included pCR rate in patients with PIK3CA/AKT1/PTEN-altered tumors and pre-surgery response rates by magnetic resonance imaging (MRI)., Results: pCR rates with ipatasertib versus placebo were 17% versus 13%, respectively, in the ITT population (N = 151), 16% versus 13% in the immunohistochemistry PTEN-low population (N = 35), and 18% versus 12% in the PIK3CA/AKT1/PTEN-altered subgroup (N = 62). Rates of overall and complete response (CR) by MRI favored ipatasertib in all three populations (CR rate 39% versus 9% in the PIK3CA/AKT1/PTEN-altered subgroup). Ipatasertib was associated with more grade ≥3 adverse events (32% versus 16% with placebo), especially diarrhea (17% versus 1%). Higher cycle 1 day 8 (C1D8) immune score was significantly associated with better response only in placebo-treated patients. All ipatasertib-treated patients with low immune scores and a CR had PIK3CA/AKT1/PTEN-altered tumors., Conclusions: Adding ipatasertib to 12 weeks of paclitaxel for early TNBC did not clinically or statistically significantly increase pCR rate, although overall response rate by MRI was numerically higher with ipatasertib. The antitumor effect of ipatasertib was most pronounced in biomarker-selected patients. Safety was consistent with prior experience of ipatasertib-paclitaxel. A T-cell-rich environment at C1D8 had a stronger association with improved outcomes in paclitaxel-treated patients than seen for baseline tumor-infiltrating lymphocytes. This dependency may be overcome with the addition of AKT inhibition, especially in patients with PIK3CA/AKT1/PTEN-altered tumors., Clinicaltrials.gov: NCT02301988., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Circulating biomarkers in blood may provide an interesting alternative to risky tissue biopsies in the diagnosis and follow-up of glioblastoma patients. We have assessed MGMT methylation status in blood and tissue samples from unresected glioblastoma patients who had been included in the randomized GENOM-009 trial. Paired blood and tissue samples were assessed by methylation-specific PCR (MSP) and pyrosequencing (PYR). After establishing the minimum PYR cut-off that could yield a significant difference in overall survival, we assessed the sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the analyses. Methylation could be detected in cfDNA by both MSP and PYR but with low concordance with results in tissue. Sensitivity was low for both methods (31% and 38%, respectively), while specificity was higher for MSP in blood than for PYR in plasma (96% vs 76%) and NPV was similar (56 vs 57%). Concordance of results in tissue by MSP and PYR was 84.3% (P < 0.001) and correlated with outcome. We conclude that detection of cfDNA in the blood of glioblastoma patients can be an alternative when tumor tissue is not available but methods for the detection of cfDNA in blood must improve before it can replace analysis in tumor tissue.