Everolimus plus endocrine therapy beyond CDK4/6 inhibitors progression for HR+ /HER2- advanced breast cancer: a real-world evidence cohort.

PURPOSE: Everolimus in combination with endocrine therapy (ET) was formerly approved as 2nd-line therapy in HR(+)/HER2(-) advanced breast cancer (aBC) patients (pts) progressing during or after a non-steroidal aromatase inhibitor (NSAI). Since this approval, the treatment landscape of aBC has changed dramatically, particularly with the arrival of CDK 4-6 inhibitors. Endocrine monotherapy after progression to CDK4/6 inhibitors has shown a limited progression-free survival (PFS), below 3 months. Evidence of the efficacy of everolimus plus ET after CDK4/6 inhibitors is scarce. METHODS: A retrospective observational study of patients with aBC treated with everolimus and ET beyond CDK4/6-i progression compiled from February 2015 to December 2022 in 4 Spanish hospitals was performed. Clinical and demographic data were collected from medical records. The main objective was to estimate the median progression-free survival (mPFS). Everolimus adverse events (AE) were registered. Quantitative variables were summarized with medians; qualitative variables with proportions and the Kaplan-Meier method were used for survival estimates. RESULTS: One hundred sixty-one patients received everolimus plus ET (exemestane: 96, fulvestrant: 54, tamoxifen: 10, unknown: 1) after progressing on a CDK4/6 inhibitor. The median follow-up time was 15 months (interquartile range: 1-56 months). The median age at diagnosis was 49 years (range: 35-90 years). The estimated mPFS was 6.0 months (95%CI 5.3-7.8 months). PFS was longer in patients with previous CDK4/6 inhibitor therapy lasting for > 18 months (8.7 months, 95%CI 6.6-11.3 months), in patients w/o visceral metastases (8.0 months, 95%CI 5.8-10.5 months), and chemotherapy-naïve in the metastatic setting (7.2 months, 95%CI 5.9-8.4 months). CONCLUSION: This retrospective analysis cohort of everolimus plus ET in mBC patients previously treated with a CDK4/6 inhibitor suggests a longer estimated mPFS when compared with the mPFS with ET monotherapy obtained from current randomized clinical data. Everolimus plus ET may be considered as a valid control arm in novel clinical trial designs.

Pregnancy After Breast Cancer in Young BRCA Carriers: An International Hospital-Based Cohort Study.

Importance: Young women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers. Objective: To investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers. Design, Setting, and Participants: International, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023. Exposure: Pregnancy after breast cancer. Main Outcomes and Measures: Primary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer-specific survival, overall survival, pregnancy, and fetal and obstetric outcomes. Results: Of 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer-specific survival and overall survival. Conclusions and Relevance: In this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03673306.

Outcomes and endpoints of relevance in gynecologic cancer clinical trials.

Drug development is paramount to improve outcomes in patients with gynecologic cancers. A randomized clinical trial should measure whether a clinically relevant improvement is detected with the new intervention compared with the standard of care, using reproductible and appropriate endpoints. Clinically meaningful improvements in overall survival and/or quality of life (QoL) are the gold standards to measure benefit of new therapeutic strategies. Alternative endpoints, such as progression-free survival, provide an earlier measure of the effect of the new therapeutic drug, and are not confounded by the effect of subsequent lines of therapy. Yet, its surrogacy with improved overall survival or QoL is unclear in gynecologic malignancies. Of relevance to studies assessing maintenance strategies are other time-to-event endpoints, such as progression-free survival two and time to second subsequent treatment, which provide valuable information on the disease control in the longer term. Translational and biomarker studies are increasingly being incorporated into gynecologic oncology clinical trials, as they may allow understanding of the biology of the disease, resistance mechanisms, and enable a better selection of patients who might benefit from the new therapeutic strategy. Globally, the endpoint selection of a clinical trial will differ according to the type of study, population, disease setting, and type of therapeutic strategy. This review provides an overview of primary and secondary endpoint selection of relevance for gynecologic oncology clinical trials.

Age and Breast Reconstruction.

BACKGROUND: Breast reconstruction is frequently offered to cancer patients who undergo mastectomy. Older women tend to have lower rates of reconstruction mostly due to an age-based discretion. We aimed to assess the safety of this surgery in this population. METHODS: We conducted a single-center retrospective analysis of patients who underwent breast reconstruction following mastectomy between 2015 and 2020 at "Complejo Hospitalario Universitario de Albacete." Patients were classified according to age when the reconstruction process began (group A: < 65 years-group B: > 65 years). Differences in demographics and clinical data were analyzed using Student's t test and Chi-square test. Multivariable logistic regression models were used to estimate odds ratio (OR) and confidence intervals (CIs) for surgical complications according to age group. Propensity-score matching was used as a sensitivity analysis to test consistency among results. RESULTS: We included 304 women (266: group A-38: group B). Complete reconstruction was achieved in 48.1% of patients in group A vs 10.5% in group B (P < 0.001). After adjusting for potential confounders, age was not associated with an increased risk of surgical complications, neither overall (OR 0.88, 95%CI 0.40-1.95), early (OR 1.35, 95%CI 0.58-3.13) nor late (OR 1.05, 95%CI 0.40-2.81). Radiotherapy and smoking history were significant predictors for complications in every setting. CONCLUSIONS: In our cohort, age at breast reconstruction is not associated with a higher risk of surgical complications, in contrast to radiotherapy and smoking history. Therefore, age should not be a limiting factor when considering breast reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Characterization of the perioperative changes of exosomal immune-related cytokines induced by prostatectomy in early-stage prostate cancer patients.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are relevant in prostate cancer microenvironment collaborating in tumor development. The main tumor marker used in this disease, prostate-specific antigen (PSA), does not provide information related to this tumor microenvironment. Cancer cells secrete exosomes carrying bioactive molecules contributing to MDSCs recruitment and induction. The aim of this study was to characterize the perioperative changes of exosomal cytokines relevant in MDSCs recruitment induced by prostatectomy in prostate cancer patients. METHODS: Blood was drawn from 26 early-stage prostate cancer patients before and after radical prostatectomy and from 16 healthy volunteers. Serum exosomes were separated by precipitation. Cytokines related with MDSC cell recruitment and activation CCL2, CXCL2, CXCL5, CXCL8, CXCL12, MIF, S100A9 and TGF-ß were measured in serum and serum-derived exosomes using immunometric assays. RESULTS: All cytokines were detected both in serum and exosomes, except for CXCL12, which was detected only in serum. Exosomes were enriched specially in MIF, TGF-ß and CXCL2. Presurgical MIF levels in exosomes correlated negatively with serum PSA. Also, presurgical TGF-ß decreased both in serum and exosomes as Gleason score rises. Patients presurgical exosomes had increased CCL2, CXCL5 and TGF-ß levels than exosomes from healthy controls. These differences were not observed when cytokines were analyzed in serum, except for TGF-ß. Cytokine levels of CCL2, CXCL5 decreased in patients' postsurgical exosomes, while TGF-ß further increased. On the contrary, S100A9 levels were lower in patients presurgical exosomes but increased after radical prostatectomy. CONCLUSIONS: Blood exosomal content in cytokines constitute an attractive source to evaluate MDSCs immunomodulators providing additional information related to tumor microenvironment in prostate cancer.

Dietary calcium, vitamin D, and breast cancer risk in women: findings from the SUN cohort.

PURPOSE: Epidemiological evidence concerning the relationship between calcium and vitamin D intake and breast cancer (BC) is inconclusive. Moreover, the association according to menopausal status remains unclear. We aimed to assess whether total intakes from dietary and supplemental sources of calcium and vitamin D were associated with the incidence of BC in a Mediterranean cohort. METHODS: We prospectively evaluated the association between intakes of calcium and vitamin D and BC risk among 10,812 women in the Seguimiento Universidad de Navarra (SUN) Project, a Spanish cohort of university graduates. RESULTS: During a mean follow-up of 10.7 years, 101 incident BC cases were confirmed. Evidence of a non-linear association between total calcium intake and BC risk was found (Pnon-linearity = 0.011) with risk reductions associated with higher intake up to approximately 1400 mg/day. Moderate intake [Tertile 2 (T2)] of total calcium was associated with lower overall BC risk [HR for T2 vs. Tertile 1 (T1): 0.55; 95% CI 0.33-0.91] and also among postmenopausal women (HRT2 vs. T1 = 0.38; 95% CI 0.16-0.92). Intake of vitamin D was not associated with BC risk. CONCLUSIONS: Our findings suggest an L-shaped association between total calcium intake and BC incidence. Moderate calcium intake may be associated with lower BC risk among overall and postmenopausal women, but not among premenopausal women. No evidence for any association between vitamin D intake and BC was found. Adherence to current guidelines recommendations for calcium intake may help to reduce BC risk.

Body shape trajectories and risk of breast cancer: results from the SUN ('Seguimiento Universidad De Navarra') Project.

OBJECTIVE: The aim of this study was to assess body shape trajectories in childhood and midlife in relation to subsequent risk of breast cancer (BC) in a Mediterranean cohort. DESIGN: The 'Seguimiento Universidad de Navarra' (SUN) Project is a dynamic prospective cohort study of university graduates initiated in 1999. With a group-based modelling approach, we assessed body shape trajectories from age 5 to 40 years. Multivariable Cox regression models were used to estimate the hazard ratio (HR) for BC after the age of 40 years according to the body shape trajectory. SETTING: City of Pamplona, in the North of Spain. PARTICIPANTS: 6498 women with a mean age of 40 years (sd 9). RESULTS: We identified four distinct body shape trajectories ('childhood lean-midlife increase' (19·9 %), 'childhood medium-midlife stable' (53 %), 'childhood heavy-midlife stable' (21 %) and 'childhood heavy-midlife increase' (6·1 %)). Among 54 978 women-years of follow-up, we confirmed eighty-two incident cases of BC. Women in the 'childhood lean-midlife increase' group showed a higher risk of BC (HR = 1·84, 95 % CI 1·11, 3·04) compared with women in the 'childhood medium-midlife stable' category. This association was stronger for postmenopausal BC (HR = 2·42, 95 % CI 1·07, 5·48). CONCLUSIONS: Our results suggest a role for lifetime adiposity in breast carcinogenesis.

Total polyphenol intake and breast cancer risk in the Seguimiento Universidad de Navarra (SUN) cohort.

Polyphenols are a wide family of phytochemicals present in diverse foods. They might play a role in cancer development and progression. In vivo and in vitro studies have suggested beneficial properties and potential mechanisms. We aimed to evaluate the association between total and main classes of polyphenol intake and breast cancer (BC) risk in the Seguimiento Universidad de Navarra project - a prospective Mediterranean cohort study. We included 10 713 middle-aged, Spanish female university graduates. Polyphenol intake was derived from a semi-quantitative FFQ and matching food consumption data from the Phenol-Explorer database. Women with self-reported BC were asked to return a copy of their medical report for confirmation purposes; death certificates were used for fatal cases. Cox models were fitted to estimate multivariable-adjusted hazard ratios (HR) and 95 % CI for the association between tertiles (T) of polyphenol intake and BC. After 10·3 years of median follow-up, 168 probable incident BC cases were identified, out of which 100 were confirmed. We found no association between polyphenol intake and the overall BC risk. Nevertheless, we observed a significant inverse association between total polyphenol intake and BC risk for postmenopausal women, either for probable or only for confirmed cases (HRT3 v. T1 0·31 (95 % CI 0·13, 0·77; Ptrend=0·010)). Also, phenolic acid intake was inversely associated with postmenopausal BC. In summary, we observed no significant association between total polyphenol intake and BC risk. Despite a low number of incident BC cases in our cohort, higher total polyphenol intake was associated with a lower risk of postmenopausal BC.

Areas of Interest and Stigmatic Attitudes of the General Public in Five Relevant Medical Conditions: Thematic and Quantitative Analysis Using Twitter.

BACKGROUND: Twitter is an indicator of real-world performance, thus, is an appropriate arena to assess the social consideration and attitudes toward psychosis. OBJECTIVE: The aim of this study was to perform a mixed-methods study of the content and key metrics of tweets referring to psychosis in comparison with tweets referring to control diseases (breast cancer, diabetes, Alzheimer, and human immunodeficiency virus). METHODS: Each tweet's content was rated as nonmedical (NM: testimonies, health care products, solidarity or awareness and misuse) or medical (M: included a reference to the illness's diagnosis, treatment, prognosis, or prevention). NM tweets were classified as positive or pejorative. We assessed the appropriateness of the medical content. The number of retweets generated and the potential reach and impact of the hashtags analyzed was also investigated. RESULTS: We analyzed a total of 15,443 tweets: 8055 classified as NM and 7287 as M. Psychosis-related tweets (PRT) had a significantly higher frequency of misuse 33.3% (212/636) vs 1.15% (853/7419; P<.001) and pejorative content 36.2% (231/636) vs 11.33% (840/7419; P<.001). The medical content of the PRT showed the highest scientific appropriateness 100% (391/391) vs 93.66% (6030/6439; P<.001) and had a higher frequency of content about disease prevention. The potential reach and impact of the tweets related to psychosis were low, but they had a high retweet-to-tweet ratio. CONCLUSIONS: We show a reduced number and a different pattern of contents in tweets about psychosis compared with control diseases. PRT showed a predominance of nonmedical content with increased frequencies of misuse and pejorative tone. However, the medical content of PRT showed high scientific appropriateness aimed toward prevention.

Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry.

BACKGROUND: The choice of chemotherapy in HER2-negative gastric cancer is based on centre's preferences and adverse effects profile. No schedule is currently accepted as standard, nor are there any factors to predict response, other than HER2 status. We seek to evaluate whether Lauren type influences the efficacy of various chemotherapies and on patient overall survival (OS). METHODS: We have conducted a multicenter study in 31 hospitals. The eligibility criteria include diagnosis of stomach or gastroesophageal junction adenocarcinoma, HER2 negativity, and chemotherapy containing 2-3 drugs. Cox proportional hazards regression adjusted for confounding factors, with tests of 'treatment-by-histology' interaction, was used to estimate treatment effect. RESULTS: Our registry contains 1303 tumours analysable for OS end points and 730 evaluable for overall response rate (ORR). A decrease in ORR was detected in the presence of a diffuse component: odds ratio 0.719 (95% confidence interval (CI), 0.525-0.987), P=0.039. Anthracycline- or docetaxel-containing schedules increased ORR only in the intestinal type. The diffuse type displayed increased mortality with hazard ratio (HR) of 1.201 (95% CI, 1.054-1.368), P=0.0056. Patients receiving chemotherapy with docetaxel exhibited increased OS limited to the intestinal type: HR 0.65 (95% CI, 0.49-0.87), P=0.024, with no increment in OS for the subset having a diffuse component. With respect to progression-free survival (PFS), a significant interaction was seen in the effect of docetaxel-containing schedules, with better PFS limited to the intestinal type subgroup, in the comparison against any other schedule: HR 0.65 (95% CI, 0.50-0.85), P=0.015, and against anthracycline-based regimens: HR 0.64 (95% CI, 0.46-0.88), P=0.046. CONCLUSIONS: As a conclusion, in this registry, Lauren classification tumour subtypes predicted survival and responded differently to chemotherapy. Future clinical trials should stratify effect estimations based on histology.

Prognostic significance of performing universal HER2 testing in cases of advanced gastric cancer.

BACKGROUND: Trastuzumab significantly improves overall survival (OS) when added to cisplatin and fluoropyrimidine as a treatment for HER2-positive advanced gastric cancers (AGC). The aim of this study was to evaluate the impact of the gradual implementation of HER2 testing on patient prognosis in a national registry of AGC. METHODS: This Spanish National Cancer Registry includes cases who were consecutively recruited at 28 centers from January 2008 to January 2016. The effect of missing HER2 status was assessed using stratified Cox proportional hazards (PH) regression. RESULTS: The rate of HER2 testing increased steadily over time, from 58.3 % in 2008 to 92.9 % in 2016. HER2 was positive in 194 tumors (21.3 %). In the stratified Cox PH regression, each 1 % increase in patients who were not tested for HER2 at the institutions was associated with an approximately 0.3 % increase in the risk of death: hazard ratio, 1.0035 (CI 95 %, 1.001-1.005), P = 0.0019. Median OS was significantly lower at institutions with the highest proportions of patients who were not tested for HER2. CONCLUSION: Patients treated at centers that took longer to implement HER2 testing exhibited worse clinical outcomes. The speed of implementation behaves as a quality-of-care indicator. Reviewed guidelines on HER2 testing should be used to achieve this goal in a timely manner.

Chronic exposure to IFNα drives medullar lymphopoiesis towards T-cell differentiation in mice.

Interferon-α is a potent antiviral agent and a vigorous adjuvant in the induction of T-cell responses but its use is limited by hematologic toxicity. Interferon-α alters hematopoietic stem cell dormancy and impairs myelocytic and erythrocytic/megakaryocytic differentiation from hematopoietic progenitors. However, the effect of chronic interferon-α exposure on hematopoietic precursors has still not been well characterized. Here, we transduced the liver of mice with an adenoassociated vector encoding interferon-α to achieve sustained high serum levels of the cytokine. The bone marrow of these animals showed diminished long-term and short-term hematopoietic stem cells, reduction of multipotent progenitor cells, and marked decrease of B cells, but significant increase in the proportion of CD8(+) and CD4(+)CD8(+) T cells. Upon adoptive transfer to RAG(-/-) mice, bone marrow cells from interferon-α-treated animals generated CD4(+) and CD8(+) T cells while CD19(+), CD11b(+) and NK1.1(+) lineages failed to develop. These effects are associated with the transcriptional downregulation of transcription factors involved in B-cell differentiation and modulation of key factors for T-cell development. Thus, sustained interferon-α exposure causes hematopoietic stem cells exhaustion and drives common lymphoid progenitors towards T-cell generation.

Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response.

Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd's response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft  models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer.

Digging into phenotype change in mismatch repair deficient endometrial carcinoma and treatment with immune checkpoint inhibition, a case report.

•False negative cases for mismatch repair determination by immunohistochemistry may occur.•The mismatch repair phenotype in endometrial carcinoma impacts on therapeutic decision making.•Retesting for mismatch repair at relapse of endometrial carcinoma should be considered.

Associations between overall, healthful, and unhealthful low-fat dietary patterns and breast cancer risk in a Mediterranean cohort: The SUN project.

OBJECTIVES: Dietary patterns may have a greater influence on human health than individual foods or nutrients, and they are also of substantial interest in the field of breast cancer prevention. Beyond the adequate balance of macronutrients, evidence indicates that the quality of macronutrient sources may play an important role in health outcomes. We sought to examine the relationship between healthful and unhealthful low-fat dietary patterns in relation to breast cancer. METHODS: We used observational data from a Mediterranean cohort study (the Seguimiento Universidad de Navarra project). We prospectively followed 10 930 middle-aged women initially free of breast cancer during a median follow-up of 12.1 y. We calculated an overall, an unhealthful, and a healthful low-fat diet score, based on a previously validated 136-item food frequency questionnaire and grouped participants into tertiles. Incident breast cancer-overall and stratified by menopausal status-was the primary outcome. It was self-reported by participants and confirmed based on medical reports or consultation of the National Death Index. We used multivariable Cox regression models adjusted for potential confounders. RESULTS: During 123 297 person-years of follow-up, 150 cases of incident breast cancer were confirmed. No significant associations were observed for overall or premenopausal breast cancer. For postmenopausal women, we observed a significant association for moderate adherence to the unhealthful low-fat dietary score and postmenopausal breast cancer (comparing tertile 2 to tertile 1; hazard ratio = 2.18; 95% confidence interval, 1.15-4.13). CONCLUSIONS: In conclusion, no clear associations were observed, although more research is needed to address the association between an unhealthful dietary pattern and postmenopausal breast cancer risk.

Analysis of the association of HER-2 low carcinomas and PAM50 assay in hormone receptor positive early-stage breast cancer.

BACKGROUND: HER2-low has emerged as a new predictive biomarker in metastatic breast cancer. However, its prognostic value in early-stage carcinomas needs to be revisited. We aimed to evaluate the association of HER2-low carcinomas with PAM50 risk groups combined with clinicopathological variables in early breast cancer. METHODS: We conducted a retrospective analysis of 332 patients with early-stage breast cancer that underwent PAM50 signature analysis between 2015 and 2021at Hospital Universitario 12 de Octubre (Madrid, Spain). Clinical and pathological variables were collected from medical records. After adjusting for potential confounders, we estimated Odds Ratio (OR) and 95% confidence interval for high-risk PAM50 subgroup, comparing HER2-low versus HER2-zero carcinomas by multivariable logistic regression. P values below 0.05 were deemed statistically significant. RESULTS: 192 (57%) patients were classified as HER2-low carcinomas. Median follow-up was 34 months. Adjusted OR for high-risk PAM50 when comparing HER2-low versus HER2-zero carcinomas was 1.31 (95% CI: 0.75-2.30, p = 0.33). The multivariable model detected significant associations for Ki-67% (≥20% vs. <20%: OR = 4.03, 95% CI: 2.15-7.56, p < 0.001), T staging category (T2/T3 vs. T1: OR = 3.44, 95% CI: 1.96-6.04, p < 0.001), progesterone receptor (PR ≥ 20% vs. <20%: OR = 0.44, 95% CI: 0.23-0.83, p = 0.01), nodal staging category (N+ vs. N0: OR = 3.8, 95% CI: 1.89-7.62, p < 0.001) and histological grade (grade 2 vs. 1: OR = 2.41, 95% CI: 1.01-5.73, p = 0.04; grade 3 vs 1: OR = 5.40, 95%CI: 1.98-14.60, p = 0.001). CONCLUSIONS: In this early-stage breast cancer cohort, HER2-low was not associated with a high-risk PAM50 compared to HER2-zero carcinomas. Ki-67 ≥ 20%, T2/T3, histological grade 2/3, N+ and PR<20% were significantly associated to a high-risk PAM50.

Career and Professional Development for Young Oncologists.

Young oncologists around the globe face many challenges when it comes to their career and professional development. Aspects such as time management, work-life balance, career progression, and educational opportunities are only some of them. Professional societies have identified these challenges in this professional group and designed programs to tackle them specifically. The importance of this strategy cannot be overstated, as young oncologists, defined by most societies as oncologists under 40 years of age, compose almost 50% of the oncology workforce. On the other hand, recent surveys have shown that many young oncologists are considering alternative career paths due to burnout issues aggravated by the COVID-19 pandemic, on top of all other challenges. The virtual setting that has been forcedly introduced into our professional life has shortened distances between professionals and might have contributed to more accessible access to information and opportunities that some young oncologists could not profit from due to their traveling constraints. On the other hand, this virtual setting has shown us the asymmetries in opportunities for these professionals. Knowledgeable of all this, we summarize in this article some of the career and professional development offers available to all young oncologists, which we consider could help them deal with current and future challenges.

p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor-positive breast cancer.

CDK4/6 inhibitors benefit a minority of patients who receive them in the breast cancer adjuvant setting. p27Kip1 is a protein that inhibits CDK/Cyclin complexes. We hypothesized that single-nucleotide polymorphisms that impaired p27Kip1 function could render patients refractory to endocrine therapy but responsive to CDK4/6 inhibitors, narrowing the patient subpopulation that requires CDK4/6 inhibitors. We found that the p27Kip1 V109G single-nucleotide polymorphism is homozygous in approximately 15% of hormone-positive breast cancer patients. Polymorphic patients experience rapid failure in response to endocrine monotherapy compared with wild-type or heterozygous patients in the first-line metastatic setting (progression-free survival: 92 vs 485 days, P < .001); when CDK4/6 inhibitors are added, the differences disappear (progression-free survival: 658 vs 761 days, P = .92). As opposed to wild-type p27Kip1, p27Kip1 V109G is unable to suppress the kinase activity of CDK4 in the presence of endocrine inhibitors; however, palbociclib blocks CDK4 kinase activity regardless of the p27Kip1 status. p27Kip1 genotyping could constitute a tool for treatment selection.

Tumor P70S6K hyperactivation is inversely associated with tumor-infiltrating lymphocytes in triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is characterized by large heterogeneity and relative lack of available targeted therapies. To find therapeutic strategies for distinct patients with TNBC, several approaches have been used for TNBC clustering, including recently immune and phosphoproteomic patterns. Based on 70-kDa ribosomal protein S6 kinase (P70S6K)-TNBC clustering, the current study explores the immune profiling in TNBC tumors. METHODS: Stromal tumor-infiltrating lymphocytes (sTILs) were evaluated in human TNBC tumor samples. Furthermore, immunohistochemistry staining for CD8, CD4, Foxp3, and CD20 was performed in tissue microarrays (TMA) sections. RESULTS: Histological analysis showed decreased sTILs, CD20+ cells, and CD8+/CD4+ ratio in high phosphorylated P70S6K (p-P70S6K) tumors. Moreover, p-P70S6K score was directly correlated with CD4+ and Foxp3+ T cells, while it was inversely correlated with CD8+/CD4+ and CD8+/Foxp3+ ratios. CONCLUSION: sTIL infiltration and lymphocyte profiling vary in the context of hyperactivation of P70S6K in TNBC tumors.

Circulating tumor DNA reveals complex biological features with clinical relevance in metastatic breast cancer.

Liquid biopsy has proven valuable in identifying individual genetic alterations; however, the ability of plasma ctDNA to capture complex tumor phenotypes with clinical value is unknown. To address this question, we have performed 0.5X shallow whole-genome sequencing in plasma from 459 patients with metastatic breast cancer, including 245 patients treated with endocrine therapy and a CDK4/6 inhibitor (ET + CDK4/6i) from 2 independent cohorts. We demonstrate that machine learning multi-gene signatures, obtained from ctDNA, identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to what is accomplished using direct tumor tissue DNA or RNA profiling. More importantly, 4 DNA-based subtypes, and a ctDNA-based genomic signature tracking retinoblastoma loss-of-heterozygosity, are significantly associated with poor response and survival outcome following ET + CDK4/6i, independently of plasma tumor fraction. Our approach opens opportunities for the discovery of additional multi-feature genomic predictors coming from ctDNA in breast cancer and other cancer-types.