Search

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physician's choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.

In this post hoc analysis of the ASCENT study, we compared outcomes with sacituzumab govitecan (SG) vs single-agent chemotherapy in clinically important subgroups of patients with metastatic triple-negative breast cancer (mTNBC). Patients with mTNBC refractory to/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG or treatment of physician's choice (TPC) until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 by central review in patients without brain metastases. Patients with brain metastases were allowed if metastases were stable ≥4 weeks. In the intention-to-treat (ITT) population, 19% of patients were age ≥65 years; 12% were Black, and 12% had brain metastases. SG improved PFS and overall survival (OS), respectively, vs TPC in patients age ≥65 years (7.1 vs 2.4 months and 14.7 vs 8.9 months), or of Black race (5.4 vs 2.2 months and 13.8 vs 8.5 months), consistent with outcomes in the ITT population. Patients with brain metastases had numerically higher median PFS with SG vs TPC, but median OS was similar between treatment groups. SG was well tolerated and had a manageable safety profile consistent with the full safety population across all subgroups; neutropenia and diarrhea were the most common treatment-emergent adverse events. These findings confirm the meaningful clinical benefit of SG vs standard chemotherapy in patient subgroups with high unmet needs. SG should be considered an effective and safe treatment option for patients with mTNBC eligible for second-line or later therapy. ClinicalTrials.gov Number: NCT02574455., (© 2024. The Author(s).)

Research on metastatic cancer has been hampered by limited sample availability. Here we present the breast cancer post-mortem tissue donation program UPTIDER and show how it enabled sampling of a median of 31 (range: 5-90) metastases and 5-8 liquids per patient from its first 20 patients. In a dedicated experiment, we show the mild impact of increasing time after death on RNA quality, transcriptional profiles and immunohistochemical staining in tumor tissue samples. We show that this impact can be counteracted by organ cooling. We successfully generated ex vivo models from tissue and liquid biopsies from distinct histological subtypes of breast cancer. We anticipate these and future findings of UPTIDER to elucidate mechanisms of disease progression and treatment resistance and to provide tools for the exploration of precision medicine strategies in the metastatic setting., (© 2024. The Author(s).)

Methylmalonic acid (MMA), a by-product of propionate metabolism, is known to increase with age. This study investigates the potential of serum MMA concentrations as a biomarker for age-related clinical frailty in older patients with breast cancer. One hundred nineteen patients ≥ 70 years old with early-stage breast cancer were included (median age 76 years). G8 screening, full geriatric assessment, clinical parameters (i.e., estimated glomerular filtration rate (eGFR) and body mass index (BMI)), and serum sample collection were collected at breast cancer diagnosis before any therapy was administered. MMA concentrations were measured via liquid chromatography with tandem mass spectrometry. MMA concentrations significantly increased with age and eGFR (all P < 0.001) in this older population. The group with an abnormal G8 (≤ 14, 51% of patients) had significantly higher MMA levels than the group with normal G8 (> 14, 49%): 260 nmol/L vs. 188 nmol/L, respectively (P = 0.0004), even after correcting for age and eGFR (P = 0.001). Furthermore, in the detailed assessment, MMA concentrations correlated most with mobility (Eastern Cooperative Oncology Group (ECOG) Performance Status and Activities of Daily Living (ADL) tools, all P ≤ 0.02), comorbidity (Charlson Comorbidity Index (CCI) tool, P = 0.005), and polypharmacy (P < 0.001), whereas no significant associations were noted for instrumental ADL (IADL), Mini-Mental State Examination (MMSE), Geriatric Depression Scale-15 (GDS15), Mini Nutritional Assessment-Short Form (MNA-SF), and pain (all P > 0.1). In addition, our results showed that higher MMA levels correlate with poor overall survival in breast cancer patients (P = 0.003). Elevated serum MMA concentrations at initial diagnosis are significantly associated, not only with age but also independently with clinical frailty, suggesting a possible influence of MMA on clinical frailty in older patients with early-stage breast cancer., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Circulating cell-free DNA (cfDNA) fragments have characteristics that are specific to the cell types that release them. Current methods for cfDNA deconvolution typically use disease tailored marker selection in a limited number of bulk tissues or cell lines. Here, we utilize single cell transcriptome data as a comprehensive cellular reference set for disease-agnostic cfDNA cell-of-origin analysis. We correlate cfDNA-inferred nucleosome spacing with gene expression to rank the relative contribution of over 490 cell types to plasma cfDNA. In 744 healthy individuals and patients, we uncover cell type signatures in support of emerging disease paradigms in oncology and prenatal care. We train predictive models that can differentiate patients with colorectal cancer (84.7%), early-stage breast cancer (90.1%), multiple myeloma (AUC 95.0%), and preeclampsia (88.3%) from matched controls. Importantly, our approach performs well in ultra-low coverage cfDNA datasets and can be readily transferred to diverse clinical settings for the expansion of liquid biopsy., (© 2024. The Author(s).)

Inflammatory breast cancer (IBC) is a rare (1%-5%), aggressive form of breast cancer, accounting for approximately 10% of breast cancer mortality. In the localized setting, standard of care is neoadjuvant chemotherapy (NACT) ± anti-HER2 therapy, followed by surgery. Here we investigated associations between clinicopathologic variables, stromal tumor-infiltrating lymphocytes (sTIL), and pathologic complete response (pCR), and the prognostic value of pCR. We included 494 localized patients with IBC treated with NACT from October 1996 to October 2021 in eight European hospitals. Standard clinicopathologic variables were collected and central pathologic review was performed, including sTIL. Associations were assessed using Firth logistic regression models. Cox regressions were used to evaluate the role of pCR and residual cancer burden (RCB) on disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS). Distribution according to receptor status was as follows: 26.4% estrogen receptor negative (ER-)/HER2-; 22.0% ER-/HER2+; 37.4% ER+/HER2-, and 14.1% ER+/HER2+. Overall pCR rate was 26.3%, being highest in the HER2+ groups (45.9% for ER-/HER2+ and 42.9% for ER+/HER2+). sTILs were low (median: 5.3%), being highest in the ER-/HER2- group (median: 10%). High tumor grade, ER negativity, HER2 positivity, higher sTILs, and taxane-based NACT were significantly associated with pCR. pCR was associated with improved DFS, DRFS, and OS in multivariable analyses. RCB score in patients not achieving pCR was independently associated with survival. In conclusion, sTILs were low in IBC, but were predictive of pCR. Both pCR and RCB have an independent prognostic role in IBC treated with NACT., Significance: IBC is a rare, but very aggressive type of breast cancer. The prognostic role of pCR after systemic therapy and the predictive value of sTILs for pCR are well established in the general breast cancer population; however, only limited information is available in IBC. We assembled the largest retrospective IBC series so far and demonstrated that sTIL is predictive of pCR. We emphasize that reaching pCR remains of utmost importance in IBC., (© 2024 The Authors; Published by the American Association for Cancer Research.)

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.

What Is This Summary About?: A medicine called sacituzumab govitecan (brand name TRODELVY ® ) has been proven to be an effective treatment for metastatic triple-negative breast cancer (mTNBC for short). Metastatic breast cancer is cancer that has spread to other parts of the body. In mTNBC, the breast cancer cells do not have 3 common proteins on the cell surface, called receptors. mTNBC is more difficult to treat and more likely to come back than other types of breast cancer. The ASCENT study showed that participants with mTNBC treated with sacituzumab govitecan had a higher likelihood of living longer and delayed progression (worsening) of their cancer than those treated with standard chemotherapy . Here, we summarize the quality of life of participants with mTNBC in the ASCENT study. We compared quality of life between 236 participants treated with sacituzumab govitecan and 183 participants treated with standard chemotherapy. All participants previously received 2 or more chemotherapies that no longer controlled their cancer., What Are the Key Takeaways?: This analysis showed that participants treated with sacituzumab govitecan had better overall quality of life than participants treated with standard chemotherapy. They also had better "physical functioning", which is the ability to walk and do physical activities. Participants treated with sacituzumab govitecan maintained their overall quality of life for a longer time than those treated with standard chemotherapy. Participants treated with sacituzumab govitecan had less pain and were less tired than those treated with standard chemotherapy. On the other hand, participants treated with sacituzumab govitecan had worse diarrhea (loose or watery stools) and were more likely to have nausea/vomiting (feel sick or throw up) than participants treated with standard chemotherapy., What Were the Main Conclusions Reported by the Researchers?: Participants treated with sacituzumab govitecan had a higher likelihood of living longer and delayed progression (worsening) of their cancer. Participants also had a better overall quality of life, which was maintained (did not get worse) for a longer time. However, they experienced worsening of diarrhea and/or nausea/vomiting. Clinical Trial Registration: NCT02574455 (ASCENT) (ClinicalTrials.gov).

Purpose: We aimed to assess the impact of surgery of primary tumor in overall survival (OS) of women with de novo metastatic breast cancer., Methods: Nationwide, population-based retrospective cohort study of women diagnosed with de novo metastatic breast cancer in Belgium, between Jan/2010-Dec/2014. Data was obtained from the Belgian Cancer Registry and administrative databases. "Surgery" group was defined by surgery of primary tumor up to nine months after diagnosis. We excluded women who did not receive systemic treatment or did not complete nine months follow-up after diagnosis. All the subsequent analyses reporting on overall survival and the stratified outcome analyses were performed based on this nine-month landmark cohort. OS was estimated using Kaplan-Meier method and compared using adjusted Cox proportional hazards models controlling for confounders with 95% confidence intervals (CI). We performed a stratified analysis according to surgery timing and a propensity score matching analysis., Results: 1985 patients, 534 (26.9%) in the "Surgery" and 1451 (73.1%) in the "No Surgery" group. Patients undergoing surgery were younger (p < 0.001), had better performance status (PS) (p < 0.001), and higher proportion of HER2-positive and triple-negative breast cancer (p = 0.012). Median follow-up was 86.0 months (82.6-88.5). Median OS was 60.1 months (57.1-68.2) in the "Surgery" vs. 41.9 months (39.8-44.2) in the "No Surgery" group (adjusted HR 0.56; 0.49-0.64). OS was similar when surgery was performed upfront or after systemic treatment. Propensity score matching analysis confirmed the same findings., Conclusion: Among patients receiving systemic treatment for de novo metastatic breast cancer and surviving nine months or more, those who received surgery of the primary tumor within nine months of diagnosis have longer subsequent survival than those who did not., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chemo-immunotherapy is the first-line standard of care for patients with PD-L1 positive metastatic triple-negative breast cancer (mTNBC). SYNERGY (NCT03616886) is a dose-finding phase I and a randomized phase II, open-label trial evaluating if targeting the immunosuppressive adenosine pathway can enhance the antitumor activity of chemo-immunotherapy. The phase I part included 6 patients with untreated locally-advanced or mTNBC to determine the safety and recommended phase II dose of the anti-CD73 antibody oleclumab in combination with the anti-PD-L1 durvalumab and 12 cycles of weekly carboplatin and paclitaxel. In the phase II part, 127 women were randomized 1:1 to receive chemo-immunotherapy, with (arm A) or without (arm B) oleclumab. The primary endpoint was the clinical benefit rate at week 24, defined as stable disease, partial or complete response per RECIST v1.1. Secondary endpoints included objective response rate, duration of response, survival outcomes (progression-free survival and overall survival), and safety. The trial did not meet its primary endpoint, as the 24-week clinical benefit rate was not significantly improved by adding oleclumab (43% vs. 44%, p = 0.61). Exploratory median progression-free survival was 5.9 months in arm A as compared to 7.0 months in arm B (p = 0.90). The safety profile was manageable in both arms., (© 2023. The Author(s).)

There is an urgent need for new and better biomarker modalities to estimate the risk of recurrence within the luminal-like breast cancer (BC) population. Molecular diagnostic tests used in the clinic lack accuracy in identifying patients with early luminal BC who are likely to develop metastases. This study provides proof of concept that various liquid biopsy read-outs could serve as valuable candidates to build a multi-modal biomarker model distinguishing, already at diagnosis, between early metastasizing and non-metastasizing patients. All these blood biomarkers (chemokines, microRNAs, leukemia inhibitory factor, osteopontin, and serum-induced functional myeloid signaling responses) can be measured in baseline plasma/serum samples and could be added to the existing prognostic factors to improve risk stratification and more patient-tailored treatment in early luminal BC., (© 2023. The Author(s).)

Purpose: Invasive lobular carcinoma (ILC) represents up to 15% of all breast carcinomas. While the proportion of women with overweight and obesity increases globally, the impact of body mass index (BMI) at primary diagnosis on clinicopathological features of ILC and the prognosis of the patients has not been investigated yet., Patients and Methods: We performed a multicentric retrospective study including patients diagnosed with non-metastatic pure ILC. The association of BMI at diagnosis with clinicopathological variables was assessed using linear or multinomial logistic regression. Univariable and multivariable survival analyses were performed to evaluate the association of BMI with disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS)., Results: The data of 2856 patients with ILC and available BMI at diagnosis were collected, of which 2570/2856 (90.0%) had oestrogen receptor (ER)-positive and human epidermal growth factor receptor (HER2) not amplified/overexpressed (ER+/HER2-) ILC. Of these 2570 patients, 80 were underweight (3.1%), 1410 were lean (54.9%), 712 were overweight (27.7%), and 368 were obese (14.3%). Older age at diagnosis, a higher tumour grade, a larger tumour size, a nodal involvement, and multifocality were associated with a higher BMI. In univariable models, higher BMI was associated with worse outcomes for all end-points (DFS: hazard ratio (HR) 1.21, 95CI 1.12-1.31, p value<0.01; DRFS: HR 1.25, 95CI 1.12-1.40, p value<0.01; OS: HR 1.25, 95CI 1.13-1.37, p value<0.01). This association was not statistically significant in multivariable analyses (DFS: HR 1.09, 95CI 0.99-1.20, p value 0.08; DRFS: HR 1.03, 95CI 0.89-1.20, p value 0.67; OS: HR 1.11, 95CI 0.99-1.24, p value 0.08), whereas grade, tumour size, and nodal involvement were still prognostic for all end-points., Conclusion: Worse prognostic factors such as higher grade, larger tumour size, and nodal involvement are associated with higher BMI in ER+/HER2- ILC, while there was no statistical evidence for an independent prognostic role for BMI. Therefore, we hypothesise that the effect of BMI on survival could be mediated through its association with these clinicopathological variables., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients' body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring., (© 2023. The Author(s).)

Introduction: Anti-HER2 antibody-drug conjugates (ADCs) have shown important efficacy in HER2-low metastatic breast cancer (mBC). Criteria for receiving ADCs are based on a single assay on the primary tumour or a small metastatic biopsy. We assessed the intra-patient inter-metastasis heterogeneity of HER2-low status in HER2-negative mBC., Patients and Methods: We included samples of 10 patients (7 ER-positive and 3 ER-negative) donated in the context of our post-mortem tissue donation program UPTIDER. Excisional post-mortem biopsies of 257 metastases and 8 breast tumours underwent central HER2 immunohistochemistry (IHC), alongside 41 pre-mortem primary or metastatic samples. They were classified as HER2-zero, HER2-low (HER2-1+ or HER2-2+, in situ hybridisation [ISH] negative) or HER2-positive (HER2-3+ or HER2-2+, ISH-positive) following ASCO/CAP guidelines 2018. HER2-zero was further subdivided into HER2-undetected (no staining) and HER2-ultralow (faint staining in ≤10% of tumour cells)., Results: Median post-mortem interval was 2.5 h. In 8/10 patients, HER2-low and HER2-zero metastases co-existed, with the proportion of HER2-low lesions ranging from 5% to 89%. A total of 32% of metastases currently classified as HER2-zero were HER2-ultralow. Intra-organ inter-metastasis heterogeneity of HER2-scores was observed in the liver in 3/6 patients. Patients with primary ER-positive disease had a higher proportion of HER2-low metastases as compared to ER-negative disease (46% versus 8%, respectively). At the metastasis level, higher percentages of ER-expressing cells were observed in HER2-low or -ultralow as compared to HER2-undetected metastases., Conclusions: Important intra-patient inter-metastasis heterogeneity of HER2-low status exists. This questions the validity of HER2-low in its current form as a theranostic marker., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TG, MDS, FR, KVB, MM, AM, H-LN, EI, SL, AP, GZ, FM, SVB, AS, IN, PN, WVDB, GF, CD: no conflicts to declare. KP: research grants paid to institution: MSD and Sanofi, speaker fees and honoraria for consultancy and advisory board functions: Astra Zeneca, Eli Lilly, Exact Sciences, Focus Patient, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, speaker fees and honoraria for consultancy and advisory board functions paid to institution: Astra Zeneca, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, stock options: Need Inc, travel grants: Astra Zeneca, Novartis, Pfizer, PharmaMar, Roche. HW: his institution received financial compensation on his behalf for advisory boards, lecture fees and/or consultancy fees from Immutep Pty, MSD, Astrazenca, Daiichi, AbbVie, Lilly, Roche, EISAI, Pfizer, Sirtex, Gilead. He received travel support from Pfizer and Roche., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: This systematic review and meta-analysis aimed to evaluate the immune response to anti-SARS-CoV-2 prime-vaccination in patients with cancer., Methods: We performed a systematic literature search using PubMed, Embase, and Cochrane Library until 28/09/2021, and conference proceedings from ASCO and ESMO 2021 annual meetings. We screened for observational or interventional studies including subjects ≥ 16 years old with cancer diagnosis who were vaccinated against SARS-CoV-2. Prime-vaccination was defined as one dose of Ad26.COV2-S vaccine or two doses of BNT162b2, mRNA-1273, ChAdOx1-S or inactivated SARS-CoV-2 vaccine. The outcomes were humoral and adaptive immune responses (proportion of subjects with positive titers of antibody anti-SARS-CoV-2 spike protein and anti-SARS-CoV-2 cellular responses, respectively)., Results: We included 89 records reporting data from 30,183 subjects. The overall seropositive rate within the first month after complete anti-SARS-CoV-2 prime-vaccination was 80% [95% confidence interval (CI), 72-86%], 60% (95%CI, 53-67%) in patients with hematological malignancies (HM) versus 94% (95%CI, 88-97%) in patients with solid malignancies (SM). The diagnosis of HM was significantly associated with a lower seropositive rate on multivariate meta-regression (odds ratio 0.35, 95% CI 0.18-0.69, HM versus both, p = 0.002). The overall humoral response was 49% (95% CI, 42-56%) after incomplete prime-vaccination and 79% (95% CI, 70-86%) at 2 months after complete prime-vaccination. These responses were also lower in patients with HM at these time points. The overall cellular response rate at any time after vaccination was 61% (95% CI, 44-76%)., Conclusion: This meta-analysis provides compelling evidence of humoral and adaptive immune responses against SARS-CoV-2 in patients with cancer, which last for at least 2 months following complete prime-vaccination., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Triple-negative breast cancer (TNBC) is a disease with often an aggressive course and a poor prognosis compared to other subtypes of breast cancer. TNBC accounts for approximately 10%-15% of all diagnosed breast cancer cases and represents a high unmet need in the field. Up to just a few years ago, chemotherapy was the only systemic treatment option for this subtype (1). To date, TNBC is considered a heterogeneous disease. One of the existing classifications is based on the analysis of mRNA expression in 587 TNBC cases, in which Lehman et al. proposed six subtypes of TNBC as follows: two basal-like (BL1 and BL2) subtypes, a mesenchymal (M) subtype, a mesenchymal stem-like (MSL) subtype, an immunomodulatory (IM) subtype, and a luminal androgen receptor (LAR) subtype (2). Later studies have demonstrated that the IM and MSL subtypes do not correlate with independent subtypes but reflect background expression by dense infiltration of tumor-infiltrating lymphocytes (TILs) or stromal cells. According to this finding, the classification of TNBC has been revised into the following four subtypes: basal 1, basal 2, LAR, and mesenchymal subtypes (3). Over the last years, several new strategies have been investigated for the treatment of patients with TNBC. Among them, immunotherapy, antibody drug conjugates, new chemotherapy agents, and targeted therapy have been and are currently being developed. The present article aims to provide an updated overview on the different treatment options that are now available or are still under investigation for patients with TNBC., Competing Interests: Lazar S. Popovic: Speaking fee and/or advisory board: Roche, MSD, BMS, Astra Zeneca, Pfizer, Novartis, Gilead, Sandoz, Takeda, Astellas, Janssen, Sanofi, Abbvie, Merck, Lilly (all outside of submitted work). Gorana Matovina Brko: Speaking fee and travel support: Roche, Pfizer, Novartis, Astellas, Janssen, Sanofi, Merck (all outside of submitted work). Maja Popovic Speaking fee and travel support: Roche, BMS, Pfizer, Merck, Takeda, Astellas, Janssen (all outside of submitted work). Kevin Punie: Travel support from AstraZeneca, Pfizer, PharmaMar and Roche (outside the submitted work). His institution received honoraria for advisory/consultancy roles for AstraZeneca, Eli Lilly, Gilead Sciences, Novartis, Pfizer, Pierre Fabre, Roche, Teva and Vifor Pharma, Speaker fees for Eli Lilly, Medscape, MSD, Mundi Pharma, Novartis, Pfizer and Roche, and Research funding from MSD and Sanofi (all outside the submitted work). Ana Cvetanovic: Speaking fee and/or advisory board: Roche, MSD, Astra Zeneca, Pfizer, Novartis, Lilly (all outside of submitted work). Matteo Lambertini acted as a consultant for Roche, Pfizer, Lilly, MSD, Seagen, Gilead, AstraZeneca and Novartis, and received honoraria from Sandoz, Takeda, Ipsen, Roche, Lilly, Pfizer and Novartis (all outside the submitted work)., (© 2023 Popovic et al.)

Approximately 10% of breast cancers are associated with the inheritance of a pathogenic variant (PV) in one of the breast cancer susceptibility genes. Multiple breast cancer predisposing genes, including TP53, are responsible for the increased breast cancer risk. Tumor protein-53 (TP53) germline PVs are associated with Li-Fraumeni syndrome, a rare autosomal dominant inherited cancer predisposition syndrome associated with early-onset pediatric and multiple primary cancers such as soft tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinomas and leukemias. Women harboring a TP53 PV carry a lifetime risk of developing breast cancer of 80-90%. The aim of the present narrative review is to provide a comprehensive overview of the criteria for offering TP53 testing, prevalence of TP53 carriers among patients with breast cancer, and what is known about its prognostic and therapeutic implications. A summary of the current indications of secondary cancer surveillance and survivorship issues are also provided. Finally, the spectrum of TP53 alteration and testing is discussed. The optimal strategies for the treatment of breast cancer in patients harboring TP53 PVs poses certain challenges. Current guidelines favor the option of performing mastectomy rather than lumpectomy to avoid adjuvant radiotherapy and subsequent risk of radiation-induced second primary malignancies, with careful consideration of radiation when indicated post-mastectomy. Some studies suggest that patients with breast cancer and germline TP53 PV might have worse survival outcomes compared to patients with breast cancer and wild type germline TP53 status. Annual breast magnetic resonance imaging (MRI) and whole-body MRI are recommended as secondary prevention., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Eva Blondeaux reports research grant (to the Institution) from Gilead to pursue research effort in the field of TP53 pathogenic variants. Kevin Punie reports honoraria for consultancy/advisory roles from Astra Zeneca, Eli Lilly, Exact Sciences, Focus Patient, Gilead Sciences, MSD, Novartis, Pfizer, Roche, Seagen; honoraria for consultancy/advisory roles paid to my institution from Astra Zeneca, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, Roche, Seagen. Research funding paid to my institution from Sanofi and MSD. Stock options: Need Inc. Travel support: Astra Zeneca, Novartis, Pfizer, PharmaMar, Roche. Carmine De Angelis reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, and GSK and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Seagen, and GSK, Travel Grants from Gilead and research support (to the Institution) from Novartis outside the submitted work. Sabine C. Linn reports an advisory role for AstraZeneca and Daiichi Sankyo Europe GmbH (paid to the institution), travel and accommodation expenses from Daiichi Sankyo Europe GmbH, and research support (to the institution) from Genentech/Roche, AstraZeneca, Bristol Myers Squibb, Tesaro (now GSK), Merck, Immunomedics (now Gilead), Eurocept Pharmaceuticals, Agendia, and Novartis. Mara Cruellas reports speaker honoraria from Roche and Astrazeneca. Shani Paluch-Shimon reports - advisory Board consultancy, speaker’s bureau: AstraZeneca, Pfizer, Novartis, Lilly, Roche, MSD, Exact Sciences. Gilead. Travel: Roche. Research Funding: Pfizer. Matteo Lambertini reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo and Takeda, Travel Grants from Gilead and research support (to the Institution) from Gilead outside the submitted work. All the other authors declare no conflict of interest.’, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2022 S. Karger AG, Basel.)

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1 , BRCA2 and other high-risk genes with known penetrance.

Background: The antibody-drug conjugate sacituzumab govitecan (SG) prolongs progression-free survival and overall survival in patients with refractory/relapsed metastatic triple-negative breast cancer (mTNBC). Here, we investigated its effect on health-related quality of life (HRQoL)., Methods: This analysis was based on the open-label phase III ASCENT trial (NCT02574455). Adults with refractory/relapsed mTNBC who had received ≥2 prior systemic therapies (≥1 in the metastatic setting) were randomised 1:1 to SG or treatment of physician's choice (TPC; capecitabine, eribulin, vinorelbine, or gemcitabine). HRQoL was assessed on day 1 of each treatment cycle using the EORTC QLQ-C30. Score changes from baseline were analysed using linear mixed-effect models for repeated measures. Stratified Cox regressions evaluated time to first clinically meaningful change of HRQoL., Results: The analysis population comprised 236 patients randomised to SG and 183 to TPC. For global health status (GHS)/QoL, physical functioning, fatigue, and pain, changes from baseline were superior for SG versus TPC. Compared with TPC, SG was inferior regarding changes from baseline for nausea/vomiting and diarrhoea but non-inferior for other QLQ-C30 domains. Median time to first clinically meaningful worsening was longer for SG than for TPC for physical functioning (22.1 versus 12.1 weeks, P < 0.001), role functioning (11.4 versus 7.1 weeks, P < 0.001), fatigue (7.7 versus 6.0 weeks, P < 0.05), and pain (21.6 versus 9.9 weeks, P < 0.001)., Conclusions: SG was generally associated with greater improvements and delayed worsening of HRQoL scores compared with TPC. This supports the favourable profile of SG as an mTNBC treatment., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SL reports grants from Immunomedics during the conduct of the study. Outside the submitted work, SL has received grants and other from AbbVie, Amgen, AstraZeneca, and Celgene, grants, personal fees, and other from Daiichi Sankyo, grants and other from Novartis, Pfizer, and Roche, other from BMS, EirGenix, Lilly, Merck, MSD, Seagen, Prime/Medscape, PUMA, Samsung, and Pierre Fabre, grants from Teva and Vifor, and personal fees from Chugai. In addition, SL has a patent EP14153692.0 pending. DL has received consulting fees from MSD, Novartis, AstraZeneca, Roche, Immunomedics, and Pfizer and has obtained payment or honoraria from Amgen, MSD, Lilly, Novartis, BMS, and Roche. Support for attending meetings and/or travel were made to DL by Roche, MSD, AstraZeneca, and Novartis, and DL is on the Data Safety Monitoring Board or Advisory Board of MSD. SMT has obtained grants and personal fees from Immunomedics/Gilead during the conduct of the study. Outside of supported work, SMT has obtained grants and personal fees from AstraZeneca, Eli Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Exelixis, Bristol Myers Squibb, Eisai, NanoString, Sanofi, Odonate, and Immunomedics/Gilead, personal fees from Puma, Celldex, Seattle Genetics, Silverback Therapeutics, G1 Therapeutics, AbbVie, Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, Daiichi Sankyo, CytomX, Samsung Bioepis Inc., Certara, Mersana Therapeutics and grants from Cyclacel. KP has received honoraria for consultancy/advisory board functions and speaker fees from AstraZeneca, Eli Lilly, Exact Sciences, Focus Patient, Gilead Sciences, MSD, Novartis, Roche, and Seagen. KP's institution has received research grants from or had contracts with Sanofi and MSD; received consulting fees from AstraZeneca, Gilead Sciences, MSD, Novartis, Pfizer, and Roche; and received payment or honoraria from AstraZeneca, Eli Lilly, Gilead Sciences, MSD, Mundi Pharma, Novartis, Pfizer, and Roche. Support for attending meetings and/or travel was made to KP by AstraZeneca, Novartis, Pfizer, PharmaMar, and Roche. KP reports participation on a Data Safety Monitoring Board or Advisory Board of Eli Lilly, Gilead Sciences, MSD, Novartis, Pierre Fabre, Roche, Teva, and Vifor Pharma and is a board member of Belgian Society of Medical Oncology and Committee member of ESMO Young Oncologists and ESMO Resilience Task Force. KP has received equipment, materials, drugs, medical writing, gifts or other services from MSD and Gilead Sciences. MO has received grants from Immunomedics during the conduct of the study. Outside the submitted work, MO has obtained grants, personal fees, and non-financial support from Roche, grants and personal fees from Genentech, PUMA Biotechnology, Astra Zeneca, and Seattle Genetics, grants from Boehringer-Ingelheim, non-financial support from Pierre-Fabre, Eisai, GP Pharma, and Grünenthal, and grants, personal fees, and non-financial support from Novartis. HSR reports grants from Pfizer, Merck, Novartis, Lilly, Genentech, OBI, Odonate, Daiichi, Seattle Genetics, Eisai, MacroGenics, Sermonix, Immunomedics, and AstraZeneca, non-financial support from Daiichi, Mylan, Pfizer, Merck, Novartis, AstraZeneca, and MacroGenics, personal fees from Mylan, Puma, and Samsung outside the submitted work. AB has obtained grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, and Immunomedics, grants and personal fees from Biotheranostics Inc., and personal fees from Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Taiho, Sanofi, Daiichi Sankyo Pharma/Astra Zeneca, Puma, Phillips, Eli Lilly, and Foundation Medicine outside the submitted work. SAH reports contracted research with Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, Daiichi Sankyo, Genentech/Roche, Gilead, GSK, Immunomedics, Lilly, MacroGenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA, Radius, Sanofi, Seattle Genetics, Dignitana, Zymeworks, and Phoenix Molecular Designs, Ltd. and stock options with NK Max. AMB has obtained support for the present manuscript from Immunomedics/Gilead and consulting fees from Immunomedics/Gilead, Novartis, Genentech, Roche, Eisai, Merck and Athenex. KK received grants or contracts from Incyte, Novartis, Genentech, Lilly, Pfizer, Calithera, Immunomedics, Acetylon, Seattle Genetics, Amgen, Zeno, and CytomX, consulting fees from Lilly, Pfizer, Novartis, Eisai, AstraZeneca, Genentech, Immunomedics, Merck, Seattle Genetics, Cyclacel, and OncoSec Medical, payment or honoraria from Lilly, and support for attending meetings and/or travel from Lilly, AstraZeneca, and Pfizer. KK is a member of the steering committee at Immunomedics, AstraZeneca, and Genentech. Other financial or non-financial interests of KK include spouse (employee) with Grail, Array, and Pfizer. JC holds consulting/advisor roles at Roche, Celgene, Celestial, AstraZeneca, Biothera Pharmaceuticals, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Kyowa Kirin and honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, and Daiichi Sankyo. JC receives research funding to the institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, PIQUR Therapeutics, Puma C, and Queen Mary University of London. JC reports stock, patents, and intellectual property with MEDSIR and support for travel, accommodation, expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo. JAO has obtained consulting fees from AbbVie Inc., Agendia, Amgen, Aptitude Health, AstraZeneca, Bristol-Myers Squibb, Celgene Corporation, Eisai, G1 Therapeutics, Genentech, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, PUMA Biotechnology, Prime Oncology, Roche, Seattle Genetics, and Syndax Pharmaceuticals. VD has obtained honoraria from and holds consulting/advisory roles with Daiichi Sankyo, Gilead Sciences, MSD, Pierre Fabre Oncologie, Roche/Genentech, Novartis, Lilly, Pfizer, AstraZeneca, Eisai, AbbVie, and Seagen. VD reports participation in speakers' bureaus for and support for travel, accommodation, and expenses from Gilead, Roche, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, and Seagen. LAC reports participation on a Data Safety Monitoring Board or Advisory Board of Sanofi Aventis, Novartis, Genentech/Roche, GSK, AstraZeneca/Daiichi Sanyo, and Aptitude Health. Other financial or non-financial interests of LAC includes spouse serving on the board of Falcon Therapeutics and spouse involvement in neural stem cell therapy patent. LG has received grants or contracts from Zymeworks and Revolution Medicines, consulting fees from Forty Seven (CD47), Genenta, METIS Precision Medicine, Novartis, Odonate Therapeutics, Revolution Medicines, Synaffix, Zymeworks, Menarini Ricerche, Amgen, and Biomedical Insights Inc., payment or honoraria from Roche, and support for attending meetings and/or travel from Pfizer. LG is a co-inventor of European patent Application N.12195182.6 and 12196177.5 titled PDL-1 expression in anti-HER2 therapy-Roche (issued) and reports participation on the advisory boards of ADC Therapeutics, AstraZeneca, Celgene, Eli Lilly, G1 Therapeutics, Genentech, Genomic Health, Merck Sharp & Dohme, Oncolytics Biotech, Odonate Therapeutics, Onkaido Therapeutics, Roche, Pfizer, Taiho Pharmaceutical, Hexal Sandoz, Seattle Genetics, Synthon, Zymeworks, Sanofi Aventis. MG has received stock or stock options at Gilead as an employee. LP has obtained support for attending meetings and/or travel and stock/stock options from Gilead due to employee status. SP and LC have obtained support for the present manuscript and stock/stock options from Gilead as employees. LS is an employee of Evidera, which received payment for the statistical analysis during the conduct of the study. MP has obtained research grant funding from AstraZeneca, Immunomedics, and Lilly, funding from Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, and Synthon, and is a consultant at AstraZeneca and Roche-Genentech. MP is on the advisory boards of Debiopharm, Immunomedics, Immutep, Menarini, Odonate, Roche-Genentech, Seagen, Seattle Genetics, and has obtained support as an invited speaker at AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech. MP is a member of Board of Directors at Oncolytics., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Limited data exist regarding the associations between TROP-2 protein expression, clinical-pathological characteristics, and outcome in triple-negative breast cancer (TNBC). TROP-2 expression was determined for patients diagnosed with TNBC between 2000 and 2017 by immunohistochemistry (IHC) (ab227689, Abcam) on whole slide tumor sections, and assessed as continuous and categorical variables (H-score high, 201-300, medium 100-200 and low < 100). We investigated the prognostic value of TROP-2 expression for relapse and survival, associations between TROP-2 expression and baseline patient and tumor characteristics, stromal tumor-infiltrating lymphocytes (sTILs), androgen receptor (AR), standardized mitotic index (SMI) and pathological complete response (pCR, in patients with neoadjuvant chemotherapy) were assessed. We included 685 patients with a median age at diagnosis of 54 years (range 22-90 years). After median follow-up of 9.6 years, 17.5% of patients experienced distant relapse. TROP-2 expression was high, medium and low in 97 (16.5%), 149 (25.3%) and 343 (58.2%) of patients, respectively. The presence of LVI, associated DCIS, nodal involvement, apocrine histology and AR expression were correlated with higher TROP-2 levels. There were no associations between TROP-2 expression and sTILs, time-to-event outcomes, or pCR rate after neoadjuvant chemotherapy. TROP-2 expression is not associated with sTILs level and has no prognostic value in our cohort of stage 1-3 TNBC. However, an association with histotype and AR expression was found, suggesting a histotype specific TROP-2 expression pattern with highest expression in apocrine subtype, warranting further research., (© 2022. The Author(s).)

Purpose: The aim of this study is to assess baseline mean leukocyte telomere length (TL) as a potential predictive factor for chemotherapy toxicity and a prognostic marker for long-term outcome in early breast cancer (BC) patients., Methods: 445 BC patients were selected, diagnosed between 2007 and 2010 with early BC and treated with (neo)adjuvant fluorouracil, epirubicin and cyclophosphamide (FEC) or with FEC and Docetaxel (FEC-D). RT-qPCR was performed on germline DNA samples collected at diagnosis before any treatment, to measure mean leukocyte TL. Uni- and multivariable logistic regression or Cox proportional hazard regression analyses were carried out to assess correlation between baseline TL and toxicity parameters (derived from the medical chart) or longer-term outcome., Results: Baseline TL correlated with age as expected (p = 0.005), but not with febrile neutropenia (n = 97), left ventricular ejection fraction >10% decrease (n = 17) nor other toxicity endpoints measured (all p > 0.05). TL was neither associated with overall survival, breast cancer specific survival or distant disease-free survival (all p > 0.05)., Conclusions: Baseline TL is not associated with chemotherapy-related toxicity nor long-term outcome in BC patients., Competing Interests: Declaration of Competing Interest Hans Wildiers's institution received financial compensation on his behalf for advisory boards, lecture fees and/or consultancy fees from Immutep Pty, MSD, Astrazenca Ireland, Daiichi, AbbVie, Lilly, PSI CRO AG, KCE, EISAI, Astrazeneca, Roche. Hans Wildiers's institution received an unrestricted research grant on his behalf from Roche and he received travel support from Pfizer and Roche. Christof Vulsteke: Research funding paid to institution from Merck MSD; Consulting fees from GSK, Astellas Pharma, Merck MSD, BMS, Leo-Pharma, Janssen, Cilag, Bayer, and AstraZeneca. Kevin Punie received honoraria for consultancy/advisory roles or speaker fees from Astra Zeneca, Eli Lilly, Gilead Sciences, MSD, Novartis, Roche, Seagon (personal, outside the submitted work). Kevin Punie's Institution received honoraria for consultancy/advisory roles or speaker fees from Astra Zeneca, Eli Lilly, Gilead Sciences, Medscape, MSD, Mundi Pharma, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, Teva, Vifor Pharma (paid to institution, outside the submitted work). Research funding from MSD and Sanofi (paid to institution, outside the submitted work). Travel support from Astra Zeneca, Novartis, Pfizer, PharmaMar, Roche (outside the submitted work)., (Copyright © 2022. Published by Elsevier Inc.)

New therapy options have changed the treatment landscape of early-stage triple-negative breast cancer (TNBC) in recent years. Most patients are candidates for neoadjuvant chemotherapy, which helps to downstage the tumor and tailor adjuvant systemic therapy based on pathologic response. Capecitabine, pembrolizumab, and olaparib have been incorporated into the armamentarium of adjuvant treatment for selected patients. The KEYNOTE-522 trial, that demonstrated the benefit of pembrolizumab, given in addition to neoadjuvant chemotherapy and adjuvantly after surgery, represented a paradigm shift for early-stage TNBC treatment. Pembrolizumab was continued in the adjuvant setting irrespective of response to neoadjuvant therapy, and other adjuvant therapies were not administered in the trial. Many questions were then raised on the selection of adjuvant therapy regimens for patients with residual disease (RD). Prior to the routine use of immune-checkpoint inhibitors (ICI), the value of adjuvant capecitabine for patients with RD after neoadjuvant polychemotherapy was demonstrated. Given the poor prognosis of some patients with RD after neoadjuvant chemo-immunotherapy, while the survival advantage of adding capecitabine during the adjuvant phase of pembrolizumab is unknown, it does appear safe and can be considered. Regarding patients harboring germline BRCA mutations with RD after neoadjuvant ICI-containing regimens, the combination of olaparib with pembrolizumab can be an option based on existing safety data., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Since a detailed inventory of endothelial cell (EC) heterogeneity in breast cancer (BC) is lacking, here we perform single cell RNA-sequencing of 26,515 cells (including 8433 ECs) from 9 BC patients and compare them to published EC taxonomies from lung tumors. Angiogenic ECs are phenotypically similar, while other EC subtypes are different. Predictive interactome analysis reveals known but also previously unreported receptor-ligand interactions between ECs and immune cells, suggesting an involvement of breast EC subtypes in immune responses. We also identify a capillary EC subtype (LIPEC (Lipid Processing EC)), which expresses genes involved in lipid processing that are regulated by PPAR-γ and is more abundant in peri-tumoral breast tissue. Retrospective analysis of 4648 BC patients reveals that treatment with metformin (an indirect PPAR-γ signaling activator) provides long-lasting clinical benefit and is positively associated with LIPEC abundance. Our findings warrant further exploration of this LIPEC/PPAR-γ link for BC treatment., (© 2022. The Author(s).)

Purpose: Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38 via a proprietary hydrolyzable linker. In the ASCENT study, SG improved survival versus single-agent treatment of physician's choice (TPC) in pre-treated metastatic triple-negative breast cancer (mTNBC). Hormone/HER2 receptor changes are common, particularly at relapse/metastasis. This subanalysis assessed outcomes in patients who did/did not have TNBC at initial diagnosis, before enrollment., Methods: TNBC diagnosis was only required at study entry. Patients with mTNBC refractory/relapsing after ≥ 2 prior chemotherapies were randomized 1:1 to receive SG or TPC. Primary endpoint was progression-free survival (PFS) in patients without brain metastases., Results: Overall, 70/235 (30%) and 76/233 (33%) patients who received SG and TPC, respectively, did not have TNBC at initial diagnosis. Clinical benefit with SG versus TPC was observed in this subset. Median PFS was 4.6 versus 2.3 months (HR 0.48; 95% CI 0.32-0.72), median overall survival was 12.4 versus 6.7 months (HR 0.44; 95% CI 0.30-0.64), and objective response rate (ORR) was 31% versus 4%; those who also received prior CDK4/6 inhibitors had ORRs of 21% versus 5%. Efficacy and safety for patients with TNBC at initial diagnosis were generally similar to those who did not present with TNBC at initial diagnosis., Conclusion: Patients without TNBC at initial diagnosis had improved clinical outcomes and a manageable safety profile with SG, supporting SG as a treatment option for mTNBC regardless of subtype at initial diagnosis. Subtype reassessment in advanced breast cancer allows for optimal treatment. Clinical trial registration number NCT02574455, registered October 12, 2015., (© 2022. The Author(s).)

Background: Cell-free DNA (cfDNA) analysis holds great promise for non-invasive cancer screening, diagnosis, and monitoring. We hypothesized that mining the patterns of cfDNA shallow whole-genome sequencing datasets from patients with cancer could improve cancer detection., Methods: By applying unsupervised clustering and supervised machine learning on large cfDNA shallow whole-genome sequencing datasets from healthy individuals (n = 367) and patients with different hematological (n = 238) and solid malignancies (n = 320), we identified cfDNA signatures that enabled cancer detection and typing., Results: Unsupervised clustering revealed cancer type-specific sub-grouping. Classification using a supervised machine learning model yielded accuracies of 96% and 65% in discriminating hematological and solid malignancies from healthy controls, respectively. The accuracy of disease type prediction was 85% and 70% for the hematological and solid cancers, respectively. The potential utility of managing a specific cancer was demonstrated by classifying benign from invasive and borderline adnexal masses with an area under the curve of 0.87 and 0.74, respectively., Conclusions: This approach provides a generic analytical strategy for non-invasive pan-cancer detection and cancer type prediction., Competing Interests: Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:, (© American Association for Clinical Chemistry 2022.)

Sacituzumab govitecan (SG) is an anti-Trop-2 antibody-drug conjugate with an SN-38 payload. In the ASCENT study, patients with metastatic triple-negative breast cancer (mTNBC) relapsed/refractory to ≥2 prior chemotherapy regimens (≥1 in the metastatic setting), received SG or single-agent treatment of physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine). This ASCENT safety analysis includes the impact of age and UGT1A1 polymorphisms, which hinder SN-38 detoxification. SG demonstrated a manageable safety profile in patients with mTNBC, including those ≥65 years; neutropenia/diarrhea are key adverse events (AE). Patients with UGT1A1 *28/*28 genotype versus those with 1/*28 and *1/*1 genotypes had higher rates of grade ≥3 SG-related neutropenia (59% vs 47% and 53%), febrile neutropenia (18% vs 5% and 3%), anemia (15% vs 6% and 4%), and diarrhea (15% vs 9% and 10%), respectively. Individuals with UGT1A1 *28/*28 genotype should be monitored closely; active monitoring and routine AE management allow optimal therapeutic exposure of SG., (© 2022. The Author(s).)

Purpose: To examine the relationship between baseline elevated CA 15.3 (>30 kU/L) and the prevalence of primary or secondary metastatic disease in breast cancer., Methods: We performed a retrospective, single-center cohort study on patients with newly diagnosed breast cancer and baseline CA 15.3> 30 kU/L, diagnosed between 2000-2015. Information on tumor characteristics, pre-treatment CA 15.3, staging results, treatment approach, disease recurrence and death were collected from individual medical files. For every tumor subtype, the optimal cut-off value of CA 15.3 for determining primary metastatic disease is determined., Results: Eight hundred ninety-four patients with baseline CA15.3 > 30 kU/L were included of which 38% were diagnosed with primary metastatic disease while 15% subsequently developed secondary metastatic disease, with a median follow-up of 74 months. LuminalHER2 tumors had the highest proportion of primary metastatic disease (48%), Triple Negative tumors had the highest proportion of secondary metastatic disease (24%) (p=0.008). A higher CA 15.3 value corresponds to higher risk of both primary and secondary metastatic disease (p<0.001). For the determination of primary metastatic disease, optimal cut-off values for CA 15.3 range between 44 kU/L (Triple Negative) and 59 kU/L (Luminal B)., Conclusion: In patients with newly diagnosed breast cancer and baseline elevated CA 15.3>30 kU/L, 38% presents with primary metastatic disease and 15% develops secondary metastatic disease, with a median follow-up of 74 months. Our results can help clinicians to identify patients at risk of primary or secondary metastatic disease via information on tumor subtype and baseline CA 15.3., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

PRECISION is an initiative from the Belgian Society of Medical Oncology (BSMO) in collaboration with several stakeholders, encompassing four programs that aim to boost genomic and clinical knowledge with the ultimate goal to offer patients with metastatic solid tumors molecularly guided treatments. The PRECISION 1 study has led to the creation of a clinico-genomic database. The Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) and GeNeo studies will increase the number of patients with advanced cancer that have comprehensive genotyping of their cancer. The PRECISION 2 project consists of investigator-initiated phase II studies aiming to provide access to a targeted drug for patients whose tumors harbor actionable mutations in case the matched drug is not available through reimbursement or clinical trials in Belgium., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Invasive lobular breast cancer (ILC) is the second most common type of breast cancer after invasive breast cancer of no special type (NST), representing up to 15% of all breast cancers., Design: Latest data on ILC are presented, focusing on diagnosis, molecular make-up according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) guidelines, treatment in the early and metastatic setting and ILC-focused clinical trials., Results: At the imaging level, magnetic resonance imaging-based and novel positron emission tomography/computed tomography-based techniques can overcome the limitations of currently used imaging techniques for diagnosing ILC. At the pathology level, E-cadherin immunohistochemistry could help improving inter-pathologist agreement. The majority of patients with ILC do not seem to benefit as much from (neo-)adjuvant chemotherapy as patients with NST, although chemotherapy might be required in a subset of high-risk patients. No differences in treatment efficacy are seen for anti-human epidermal growth factor receptor 2 (HER2) therapies in the adjuvant setting and cyclin-dependent kinases 4 and 6 inhibitors in the metastatic setting. The clinical utility of the commercially available prognostic gene expression-based tests is unclear for patients with ILC. Several ESCAT alterations differ in frequency between ILC and NST. Germline BRCA1 and PALB2 alterations are less frequent in patients with ILC, while germline CDH1 (gene coding for E-cadherin) alterations are more frequent in patients with ILC. Somatic HER2 mutations are more frequent in ILC, especially in metastases (15% ILC versus 5% NST). A high tumour mutational burden, relevant for immune checkpoint inhibition, is more frequent in ILC metastases (16%) than in NST metastases (5%). Tumours with somatic inactivating CDH1 mutations may be vulnerable for treatment with ROS1 inhibitors, a concept currently investigated in early and metastatic ILC., Conclusion: ILC is a unique malignancy based on its pathological and biological features leading to differences in diagnosis as well as in treatment response, resistance and targets as compared to NST., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients with triple-negative breast cancer (TNBC) who relapse early after (neo)adjuvant chemotherapy have more aggressive disease. In the ASCENT trial, sacituzumab govitecan (SG), an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38 via a hydrolyzable linker, improved outcomes over single-agent chemotherapy of physician's choice (TPC) in metastatic TNBC (mTNBC). Of 468 patients without known baseline brain metastases, 33/235 vs 32/233 patients (both 14%) in the SG vs TPC arms, respectively, received one line of therapy in the metastatic setting and experienced disease recurrence ≤12 months after (neo)adjuvant chemotherapy. SG prolonged progression-free survival (median 5.7 vs 1.5 months [HR, 0.41; 95% CI, 0.22-0.76]) and overall survival (median 10.9 vs 4.9 months [HR, 0.51; 95% CI, 0.28-0.91]) vs TPC, with a manageable safety profile in this subgroup consistent with the overall population. In this second-line setting, as with later-line therapy, SG improved survival over conventional chemotherapy for patients with mTNBC., (© 2022. The Author(s).)

Introduction: Triple negative breast cancer (TNBC) is an area of high unmet medical need in terms of new effective treatment strategies. Although breast cancer is traditionally considered a 'cold' tumor type, TNBC is the most appropriate subtype for immunotherapeutic strategies; this is due to the high level of tumor infiltrating lymphocytes, PD-L1 expression, and tumor mutational burden compared to other breast cancer subtypes., Areas Covered: This review examines the available evidence on the use of immunotherapeutic strategies in early and advanced TNBC, discusses the pitfalls and limitations often encountered in clinical research, and summarizes data on novel promising immunomodulatory approaches that have been explored in early-phase trials., Expert Opinion: PD-1-blockade is approved for stage II/III TNBC and for first-line treatment of PD-L1-positive TNBC patients with metastatic disease and should be considered standard of care. However, question marks and difficulties remain; these include the identification of predictive biomarkers to select patients who benefit from the addition of PD1-blockade and the balance between efficacy and long-term toxicity for an individual patient. Numerous treatment combinations and new immunotherapeutic strategies beyond PD1 blockade are being evaluated, thus reflecting a promising evolution towards a more personalized approach, and extended clinical benefit in TNBC. Abbreviations: Triple-negative breast cancer (TNBC); breast cancers (BCs); estrogen receptor (ER); progesterone receptor (PgR); human epidermal growth factor-2 (HER-2); basal-like 1 (BL1), basal-like 2 (BL2); mesenchymal (MES); mesenchymal stem-like (MSL); immunomodulatory (IM); luminal androgen receptor (LAR); basal-like immunosuppressed (BLIS); basal-like immune-activated (BLIA); tumor-infiltrating lymphocytes (TILs); tumor mutational burden (TMB); immune cells (ICs); immunohistochemistry (IHC); overall response rate (ORR); overall survival (OS); progression-free survival (PFS); intention-to-treat (ITT); hazard ratio (HR); confidence interval (CI); Food and Drug Administration (FDA); European Medicines Agency (EMA); immune checkpoint inhibitors (ICI); Combined Positive Score (CPS); disease control rate (DCR); neoadjuvant chemotherapy (NACT); pathological complete response (pCR); event-free survival (EFS); disease-free survival (DFS); residual cancer burden (RCB); San Antonio Breast Cancer Symposium (SABCS); antibody-drug conjugates (ADCs); PARP inhibitors (PARPi); clinical benefit rate (CBR); Histone deacetylase inhibitors (HDACi); Dendritic cell (DC); talimogene laherparepvec (TVEC); granulocyte-macrophage colony-stimulating factor (GM-CSF); mismatch repair deficiency (dMMR).

Purpose: The prevention of taxane-related toxicities at the extremities is highly important for patients' treatment and quality-of-life. Several studies endorse hand/foot-cooling using frozen gloves as a prophylactic intervention. Unlike frozen gloves, hilotherapy produces cooling at a constant temperature. Comparative data with frozen gloves are unavailable., Methods: This prospective self-controlled study explores the efficacy of hilotherapy at the right hand and foot compared to frozen gloves at the left in patients with early breast cancer treated with weekly paclitaxel 80 mg/m 2 or three-weekly docetaxel 75 mg/m 2 . Patient-reported outcomes were collected at baseline, 6, 12, 18 and 24 weeks after the start of treatment. Primary and secondary endpoints were the incidence of any-grade and ≥ grade 2 side-effects (peripheral neuropathy, pain and nail toxicities), and perceived comfort of both interventions., Results: Sixty-two patients participated. The incidence of any-grade side-effects was similar on both sides, 85.5% with hilotherapy and 90.3% with frozen gloves (p = 1.000). The incidence of ≥ grade 2 side-effects at the extremities was significantly lower with hilotherapy: 43.6% compared to 61.3% with frozen gloves (p = 0.013). Perceived comfort was significantly better for hilotherapy than for frozen gloves (p < 0.0001)., Conclusions: Compared to frozen gloves, continuous cooling of hands and feet using hilotherapy produces better prevention of ≥ grade 2 patient-reported side-effects at the extremities (peripheral neuropathy, pain and nail toxicities). Perceived comfort was significantly better for hilotherapy. From a clinical and patient perspective, hilotherapy is a better alternative for preventing clinically significant taxane-related side-effects., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: COVID-19 has had a significant impact on the well-being and job performance of oncology professionals globally. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration set out to investigate and monitor well-being since COVID-19 in relation to work, lifestyle and support factors in oncology professionals 1 year on since the start of the pandemic., Methods: An online, anonymous survey was conducted in February/March 2021 (Survey III). Key outcome variables included risk of poor well-being or distress (expanded Well-Being Index), feeling burnout (single item from expanded Well-Being Index), and job performance since COVID-19. Longitudinal analysis of responses to the series of three surveys since COVID-19 was carried out, and responses to job demands and resources questions were interrogated. SPSS V.26.0/V.27.0 and GraphPad Prism V9.0 were used for statistical analyses., Results: Responses from 1269 participants from 104 countries were analysed in Survey III: 55% (n = 699/1269) female, 54% (n = 686/1269) >40 years, and 69% (n = 852/1230) of white ethnicity. There continues to be an increased risk of poor well-being or distress (n = 464/1169, 40%) and feeling burnout (n = 660/1169, 57%) compared with Survey I (25% and 38% respectively, P < 0.0001), despite improved job performance. Compared with the initial period of the pandemic, more participants report feeling overwhelmed with workload (45% versus 29%, P < 0.0001). There remain concerns about the negative impact of the pandemic on career development/training (43%), job security (37%). and international fellowship opportunities (76%). Alarmingly, 25% (n = 266/1086) are considering changing their future career with 38% (n = 100/266) contemplating leaving the profession., Conclusion: Oncology professionals continue to face increased job demands. There is now significant concern regarding potential attrition in the oncology workforce. National and international stakeholders must act immediately and work closely with oncology professionals to draw up future-proof recovery plans., Competing Interests: Disclosure KHJL is currently funded by the Wellcome-Imperial 4i Clinical Research Fellowship, and reports speaker honorarium from Janssen, outside the submitted work. KP’s institution received speaker fees or honoraria for consultancy/advisory roles from AstraZeneca, Eli Lilly, Gilead Sciences, Medscape, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Pierre Fabre, Hoffmann La Roche, Mundipharma, PharmaMar, Seagen, Teva, and Vifor Pharma; KP’s institution received research grants from MSD and Sanofi; KP received travel support from AstraZeneca, Novartis, Pfizer, PharmaMar, and Roche; all outside the submitted work. CO reports research funding and honoraria from Roche; travel grant and honoraria from medac Pharma and Ipsen Pharma; and travel grant from PharmaMar; outside the submitted work. EÉ reports speaker honoraria, travel support and advisory board: Bayer, Roche, Servier, Amgen, Pierre-Fabre, Sanofi Aventis, MSD, and Merck Serono; outside the submitted work. TA reports personal fees from Pierre Fabre and CeCaVa; personal fees and travel grants from Bristol Myers Squibb (BMS); grants, personal fees, and travel grants from Novartis; and grants from NeraCare, Sanofi, and SkylineDx; all outside the submitted work. PG reports personal fees from Roche, MSD, BMS, Boerhinger-Ingelheim, Pfizer, AbbVie, Novartis, Lilly, AstraZeneca, Janssen, Blueprint Medicines, Takeda, Gilead, and ROVI, outside the submitted work. ML acted as a consultant for Roche, AstraZeneca, Lilly, and Novartis, and received honoraria from Theramex, Roche, Novartis, Takeda, Pfizer, Sandoz, and Lilly, outside the submitted work. CBW reports speaker honoraria, travel support, and participation in advisory boards: Bayer, BMS, Celgene, GlaxoSmithKline (GSK), Merck, Rafael, RedHil, Roche, Servier, Shire/Baxalta, Sirtex, and Taiho, as well as research support from Roche, outside the submitted work. JBAGH reports personal fees for advisory role in Neogene Tx; grants and fees paid to institution from BMS, MSD, Novartis, BioNTech, Amgen; and fees paid to institution from Achilles Tx, GSK, Immunocore, Ipsen, Merck Serono, Molecular Partners, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures, Vaximm; outside the submitted work. CH reports being Director of a private company Hardy People Ltd, outside the submitted work. SB reports research grant (institution) from AstraZeneca, Tesaro, and GSK; honoraria for advisory boards or lectures from Amgen, AstraZeneca, Genmab, Immunogen, Mersana, MSD, Merck Serono, OncXerna, Pfizer, Roche, Shattuck Labs, Clovis, Takeda outside the submitted work. KM, KK, MOC, ET, BD, and GM have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear., Methods: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes., Results: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions., Conclusion: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction., (© 2021. The Author(s).)

Background: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants., Patients and Methods: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy., Results: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group., Conclusion: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing., Competing Interests: Disclosure EdA has acted as a scientific advisory board member and has received honoraria from Roche/Genentech, Novartis, Seattle Genetics, Zodiacs, Libbs, Pierre Fabre, and Lilly; has received travel grants from Roche/GNE and GlaxoSmithKline (GSK)/Novartis; and has received research grants through his institution from Roche/GNE, AstraZeneca, GSK/Novartis, and Servier, outside the submitted work. FAP has acted as consultant for Ipsen, Roche Diagnostic, and Merck outside the submitted work. CRJ has acted as a scientific advisory board member and her institution has received honoraria from Bristol Myers Squibb (BMS), Theramex, and Roche; and her institution has received speaker's fees from Theramex and BMS, outside the submitted work. AS has acted as a consultant for Eli Lilly, Pfizer, Novartis, and Roche; has received speaker's fees from Teva, Roche, Pfizer, and Novartis; has received travel grants from Neopharm, Celgene, and Medison; and has received grant support from Novartis and Roche, outside the submitted work. CVG has acted as a consultant, as a scientific advisory board member, and has received speaker's fees from Roche, Novartis, Pfizer, Lilly, and Merck Sharp & Dohme (MSD); and has received research funding from AstraZeneca, Roche, and Pfizer, outside the submitted work. OCC has acted as a scientific advisory board member for Ascires Sistemas Genómicos; and has received grant support from Roche Diagnostics, Neomedic, and Takeda, outside the submitted work. KP has acted as a scientific advisory board member for AstraZeneca, Eli Lilly, Gilead Sciences, MSD, Novartis, Pierre Fabre, Roche, Teva, and Vifor Pharma; has acted as a consultant for AstraZeneca, Novartis, Pfizer, and Roche; has received speaker's fees from Eli Lilly, Medscape, MSD, Mundi Pharma, Novartis, Pfizer, and Roche; has received travel grants from AstraZeneca, Novartis, Pfizer, PharmaMar, and Roche, outside the submitted work. FP has acted as a scientific advisory board member and has received speaker's fees from Amgen, AstraZeneca, Daichi-Sankyo, Eisai, Eli Lilly, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Seagen, and Takeda; has received travel grants from Celgene, GlaxoSmithKline, and Roche; and has received research funding from AstraZeneca, Eisai, and Roche, outside the submitted work. ARF has received honoraria from Bayer, Daiichi Sankyo, Novartis, and Roche; and has received travel grants from Roche, outside the submitted work. JB has acted as consultant for AstraZeneca and Pfizer outside the submitted work. ID has acted as a scientific advisory board member and received grant from Roche; has received speaker's fees from Novartis; and has received travel grants from Theramex and Ferring, outside the submitted work. ML has acted as a consultant for Roche, Lilly, AstraZeneca, Exact Sciences, and Novartis; and has received honoraria from Sandoz, Roche, Lilly, Pfizer, Novartis, Ipsen, and Takeda, outside the submitted work. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10 -8 and 4.42 × 10 -8 ). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations., (© 2021. The Author(s).)

The vast majority of studies investigating immune checkpoint inhibition (ICI) in patients with breast cancer have focused on triple-negative breast cancer (TNBC). In this study, we compared the tumor immune microenvironment (TIME) between TNBC and hormone receptor-negative HER2-positive breast cancer based on a selection of immune markers at the protein level in an institutional retrospective series. Additionally, we performed a similar comparison using publicly available transcriptomics data. Altogether, the results show a comparable TIME in both groups, with possible implications for the use of ICI in patients with hormone receptor-negative HER2-positive breast tumors., (© 2021. The Author(s).)

Background: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician's choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes., Patients and Methods: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline., Results: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations., Conclusions: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup., Competing Interests: Disclosure AB: consultancy/advisory role with Biotheranostics Inc., Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Taiho, Sanofi, Daiichi Sanyo/AstraZeneca, Puma, Philips, Eli Lilly, and Foundation Medicine; research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics; travel/accommodations/expenses from Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Taiho, and Sanofi. SMT: research funding from Bristol Myers Squibb, Eisai, Immunomedics, Genentech/Roche, Pfizer, Novartis, Nektar, Merck, AstraZeneca, Eli Lilly, and Exelixis. KP: consultancy/advisory role with AstraZeneca, Eli Lilly, Novartis, Pfizer, Pierre Fabre, Hoffmann-La Roche, Vifor Pharma, and European Centre for Clinical Research Training; speaker’s bureau with Eli Lilly, Mundipharma, Novartis, Pfizer, and Hoffmann-La Roche; research funding from Sanofi; expert testimony for Hoffmann-La Roche; travel/accommodations/expenses from AstraZeneca, Novartis, Pfizer, PharmaMar, and Hoffmann-La Roche. DL: consultancy/advisory role with Novartis, Merck Sharp & Dohme (MSD), and Roche. MO: research funding from Immunomedics, Roche, Genentech, PUMA Biotechnology, AstraZeneca, Seattle Genetics, Boehringer Ingelheim, and Novartis; expenses from Roche, Genentech, PUMA Biotechnology, AstraZeneca, Seattle Genetics, and Novartis; non-financial support from Roche, Pierre Fabre, Eisai, GP Pharma, Grünenthal, and Novartis. KK: employment (spouse) with Array Biopharma, Pfizer, and Grail; consultancy/advisory role with Immunomedics, Pfizer, Eisai, Eli Lilly, Amgen, and AstraZeneca; institutional research funding from Immunomedics, Novartis, Incyte, Genentech/Roche, Eli Lilly, Pfizer, Calithera Biosciences, Acetylon, Seattle Genetics, Amgen, Zentalis Pharmaceuticals, and CytomX Therapeutics; research funding (spouse) from Array Biopharma, Pfizer, and Grail. AZ: consultancy roles with Novartis and Pfizer. PA: travel/accommodations/expenses from Boehringer Ingelheim, MacroGenics, Amvure, Synthon, Servier, G1 Therapeutics, Roche, Novartis, Amgen, Radius, MSD, and Pfizer. SS: advisory role with Immunomedics, Novartis, and Biotheranostics. EH: consultancy/advisory role with Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Eli Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, and SeaGen; institutional research funding from OncoMed, Genentech/Roche, Zymeworks, Rgenix, ArQule, Clovis, Silverback Therapeutics, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Torque, Black Diamond, Karyopharm, Infinity Pharmaceuticals, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana-Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, SeaGen, Puma Biotechnology, Compugen, TapImmune, Eli Lilly, Pfizer, H3 Biomedicine, Takeda, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, MacroGenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Polyphor, Immunogen, Plexxikon, Amgen, Akesobio Australia, and Shattuck Labs. PS: consultancy role with Immunomedics. ECG: consultancy role with Pfizer, Roche, AstraZeneca, Novartis, and Eli Lilly; speaker’s bureau with Roche, Pfizer, and Eli Lilly. TT: consultancy/advisory role with Genentech/Roche, Pfizer, AstraZeneca, Merck, Puma Biotechnology, Advaxis, Celgene, Innocrin Pharma, Genomic Health, Bristol Myers Squibb, Samsung, Athenex, Aduro Biotech, Halozyme, Daiichi Sankyo, Ionis, and Seattle Genetics; speaker’s bureau with Roche/Genentech; research funding from Eisai, Pfizer, Novartis, Innocrin Pharma, AstraZeneca, Astellas Pharma, Immunomedics, Genentech/Roche, Daiichi Sankyo, Carrick Pharm.JO: consultancy/advisory role with AbbVie, Agendia, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, Genentech, Immunomedics, Jounce Therapeutics, Eli Lilly, Merck, Novartis, Pfizer, Puma Biotechnology, Roche, and Seattle Genetics. JC: consultancy/advisory role with Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceuticals, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly, Servier, MSD, GlaxoSmithKline (GSK), Leuko, Bioasis, and Clovis Oncology; speaker’s bureau for Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Eli Lilly, MSD, and Daiichi Sankyo; institutional research funding from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, MSD, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; ownership interest in MedSIR. LV: consultancy role with Berg Pharma, Seattle Genetics, Polyphor, Immunomedics, and Osmol Therapeutics; speaker’s bureau with Eisai; contracted research with Roche, OncoTherapy Science, Arvinas, Genentech, Seattle Genetics, and Immunomedics. VD: consultancy/advisory role with Roche/Genentech, Novartis, Eli Lilly, Pfizer, AstraZeneca, Eisai, AbbVie, MSD, Daiichi Sankyo, and Seattle Genetics; speaker’s bureau for Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, and Daiichi Sankyo; travel/accommodations/expenses from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, and Daiichi Sankyo. LAC: royalties (spouse) from Falcon Therapeutics; research funding from Innocrin Pharma, Syndax, Immunomedics, Novartis, and NanoString Technologies; institutional research funding from Sanofi-Aventis, Novartis, G1 Therapeutics, Genentech/Roche, and GSK. HSR: consultancy/advisory role with Samsung and Puma; research funding from Pfizer, Novartis, Eli Lilly, Genentech/Roche, MacroGenics, OBI, Merck, Eisai, Immunomedics, Daiichi, Seattle Genetics, and Odonate; travel/accommodations/expenses from Daiichi, Mylan, Pfizer, Merck, AstraZeneca, Novartis, and MacroGenics. DMG: intellectual property rights/patent holder at Immunomedics; ownership interest with Immunomedics; other interests with Center for Molecular Medicine & Immunology. QH, MO, LMI: employment with Immunomedics. SAH: research funding from Ambrx, Amgen, Arvinas, Bayer, Daiichi Sankyo, Genentech/Roche, GSK, Immunomedics, Eli Lilly, MacroGenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA, Radius, Sanofi, Seattle Genetics, and Dignitana; ownership interest with NKMax. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In recent years, immune checkpoint inhibitors (ICPI) have become widely used for multiple solid malignancies. Reliable predictive biomarkers for selection of patients who would benefit most are lacking. Several tumor types with somatic or germline alterations in genes involved in the DNA damage response (DDR) pathway harbor a higher tumor mutational burden, possibly associated with an increased tumoral neoantigen load. These neoantigens are thought to lead to stronger immune activation and enhanced response to ICPIs. We present a series of seven patients with different malignancies with germline disease-associated variants in DDR genes ( BRCA1 , BRCA2 , CHEK2 ) responding favorably to ICPIs.

Background: Most current guidelines do not recommend the serial analysis of tumour marker CA 15.3 in the follow-up of asymptomatic patients treated for early breast cancer (EBC). These guidelines are based on small-scale studies carried out in an era with more limited treatment options than today. In our large academic centre, serial measurements of CA 15.3 are used routinely in the follow-up of EBC, whereas imaging for distant metastases is only carried out on indication., Patients and Methods: In this retrospective single-centre study, patients were included if they were treated for EBC between 1 January 2000 and 1 January 2018, diagnosed with secondary metastatic disease at least 6 months after initial surgery and had CA 15.3 available at the time of diagnosis of metastases. The primary objective was to evaluate the proportion of patients in whom metastatic disease was discovered by an increasing CA 15.3. Information on the method of metastases detection, CA 15.3 evolution and survival was collected after approval of the ethics committee., Results: At the moment of diagnosis of metastases, 451 of 730 included patients (62%) had CA 15.3 levels above the upper limit of normal (>30 kU/l). In 269 patients (37%), an increasing CA 15.3 was the first sign that led to the diagnosis of metastases. This was most frequent in luminal A-like tumours (48%) and in liver (45%) and bone (41%) localisation of metastases. By contrast, reported symptoms triggered the diagnosis of metastatic disease in 48% of the patients. Median overall survival was significantly longer when the relapse was discovered by CA 15.3 elevation versus those discovered by another trigger (abnormal clinical examination or history, abnormal laboratory tests or an incidental finding) (35 versus 22 months; P = 0.0027)., Conclusion: When CA 15.3 is systematically used in the follow-up of EBC patients, the diagnosis of metastatic disease is made in 37% by a CA 15.3 increase., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Two new antibody-drug conjugates (ADCs) containing a topoisomerase I inhibitor payload have recently emerged in the breast cancer (BC) treatment landscape. Sacituzumab govitecan-hziy (SG) is a first-in-class anti-trophoblast cell-surface antigen 2 ADC approved for pretreated metastatic triple-negative breast cancer (mTNBC) and trastuzumab deruxtecan (T-DXd) gained approval for human epidermal growth factor receptor-2 (HER2)-positive advanced BC (aBC). We aim to provide a contemporary review and the current clinical trial landscape of SG and T-DXd in BC., Materials and Methods: We conducted a literature search from Medline database through PubMed, major conference proceedings [abstracts from European Society for Medical Oncology (Breast) Congress, American Society of Clinical Oncology annual meeting, San Antonio Breast Cancer Symposium] and ClinicalTrials.gov with search terms 'sacituzumab govitecan', 'IMMU-132', 'trastuzumab deruxtecan' and 'DS-8201a' up to 21 March 2021., Results: We assessed 293 records for eligibility, of which 153 were included in this review after screening and exclusion. For SG, efficacy and safety data are available from a phase III trial in pretreated mTNBC and from a phase I/II basket study in mTNBC and hormone receptor-positive/HER2-negative aBC. Thirteen trials with pending primary analysis are ongoing with SG as single agent or in combination, of which 11 are enrolling (2/11 in the early setting). For T-DXd, efficacy/safety data are available as single agent in pretreated HER2-positive (phase Ib and phase II) and in HER2-low aBC (phase Ib), and in combination with nivolumab in HER2-low/positive aBC (phase Ib). Of 23 ongoing trials with T-DXd, 12 are open for enrollment and 3 phase III trials have completed recruitment. The distinct safety profiles of both drugs and their management are discussed., Conclusion: Given their robust single-agent activity, SG and T-DXd are expected to substantially impact treatment standards, both in and far beyond the currently approved indications. Several trials are investigating new treatment settings for both drugs, including a transition to earlier lines and combinations with other anticancer treatments such as immune checkpoint inhibitors., Competing Interests: Disclosure PN's institution received honoraria for advisory boards and research funding from AstraZeneca, Amgen, Eli Lilly, Novartis, Pfizer and Roche (all outside the submitted work). HW received travel support from Roche and Pfizer (all outside the submitted work), institution received consulting fees and honoraria from AstraZeneca, Biocartis, Lilly, Novartis, Pfizer, PUMA Biotechnology, Roche, Sirtex and Daiichii-Sankyo and unrestricted research grants from Roche and Novartis. KP received travel support from AstraZeneca, Pfizer, PharmaMar and Roche (all outside the submitted work), institution received honoraria for advisory/consultancy roles for AstraZeneca, Eli Lilly, Gilead Sciences, Novartis, Pfizer, Pierre Fabre, Roche, Teva and Vifor Pharma; speaker fees for Eli Lilly, Medscape, MSD, Mundi Pharma, Novartis, Pfizer and Roche; and research funding from Sanofi. EA has declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Quality indicators (QIs) for the management of breast cancer (BC) have been published in Europe and internationally. In Belgium, a task force was established to select measurable process indicators of systemic treatment for BC, focusing on appropriateness of delivered care. The objective of this study was to evaluate the results of the selected QIs, both nationally and among individual centres., Patients and Methods: Female Belgian residents with unilateral primary invasive BC diagnosed between 2010 and 2014 were selected from the Belgian Cancer Registry database. The national number enabled linkage with the national reimbursement database, which contains information on all reimbursed medical procedures. A total of 12 process indicators were measured on the population and hospital level. Intercentre variability was assessed by median results and interquartile ranges., Results: A total of 48  872 patients were included in the study. QIs concerning specific BC subtypes only applied to patients diagnosed in 2014 (n = 9855). Clinical stage (cStage) I patients (n = 17 116) were staged with positron emission tomography/computed tomography. Among patients who were pT1aN0 human epidermal growth factor receptor 2 (HER2) positive (n = 47), 25.5% (n = 12) received adjuvant trastuzumab. Among patients with de novo metastatic luminal A/B-like HER2-negative BC (n = 295), 17.3% (n = 51) received upfront chemotherapy. (Neo)adjuvant chemotherapy was administered in 52.4% (n = 12 592) of operated women with cStage I-III, in 37.0% (n = 1270) of operated women with cStage I-III luminal A/B-like HER2-negative BC, and in 19.1% of operated women with cStage I luminal A/B-like HER2-negative BC. In the population of operated patients with cStage I-III, of those younger than 70 years that started adjuvant endocrine therapy (n = 3591), 81.7% (n = 2932) continued treatment for ≥4.5 years. Among patients in cStage I-III older than 70 years (n = 8544), 19.0% (n = 1622) received (neo)adjuvant chemotherapy, whereas among patients with cStage I-III luminal A/B-like HER2-negative BC (n = 1388), 13.0% (n = 181) received (neo)adjuvant chemotherapy. In patients with cStage I-II luminal A/B-like HER2-negative BC older than 70 years (n = 1477), 11.6% (n = 171) were not operated and received upfront endocrine treatment., Conclusion: Well-considered QIs using population-based data can evaluate quality of care and expose disparities among treatment centres. Their use in daily practice should be implemented in all centres treating BC., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The COVID-19 pandemic has resulted in significant changes to professional and personal lives of oncology professionals globally. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration aimed to provide contemporaneous reports on the impact of COVID-19 on the lived experiences and well-being in oncology., Methods: This online anonymous survey (July-August 2020) is the second of a series of global surveys launched during the course of the pandemic. Longitudinal key outcome measures including well-being/distress (expanded Well-being Index-9 items), burnout (1 item from expanded Well-being Index), and job performance since COVID-19 were tracked., Results: A total of 942 participants from 99 countries were included for final analysis: 58% (n = 544) from Europe, 52% (n = 485) female, 43% (n = 409) ≤40 years old, and 36% (n = 343) of non-white ethnicity. In July/August 2020, 60% (n = 525) continued to report a change in professional duties compared with the pre-COVID-19 era. The proportion of participants at risk of poor well-being (33%, n = 310) and who reported feeling burnout (49%, n = 460) had increased significantly compared with April/May 2020 (25% and 38%, respectively; P < 0.001), despite improved job performance since COVID-19 (34% versus 51%; P < 0.001). Of those who had been tested for COVID-19, 8% (n = 39/484) tested positive; 18% (n = 7/39) felt they had not been given adequate time to recover before return to work. Since the pandemic, 39% (n = 353/908) had expressed concerns that COVID-19 would have a negative impact on their career development or training and 40% (n = 366/917) felt that their job security had been compromised. More than two-thirds (n = 608/879) revealed that COVID-19 has changed their outlook on their work-personal life balance., Conclusion: The COVID-19 pandemic continues to impact the well-being of oncology professionals globally, with significantly more in distress and feeling burnout compared with the first wave. Collective efforts from both national and international communities addressing support and coping strategies will be crucial as we recover from the COVID-19 crisis. In particular, an action plan should also be devised to tackle concerns raised regarding the negative impact of COVID-19 on career development, training, and job security., Competing Interests: Disclosure KHJL is currently funded by the Wellcome-Imperial 4i Clinical Research Fellowship, and reports speaker honorarium from Janssen, outside the submitted work. KP’s institution received speaker fees or honoraria for consultancy/advisory roles from AstraZeneca, Eli Lilly, Gilead Sciences, Medscape, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Pierre Fabre, Hoffmann La Roche, Mundipharma, PharmaMar, Teva, Vifor Pharma; KP’s institution received a research grant from Sanofi; KP received travel support from AstraZeneca, Novartis, Pfizer, PharmaMar and Roche; all outside the submitted work. CO reports research funding and honoraria from Roche; travel grant and honoraria from Medac Pharma and Ipsen Pharma; and travel grant from PharmaMar; outside the submitted work. TA reports personal fees from Pierre Fabre and CeCaVa; personal fees and travel grants from Bristol-Myers Squibb (BMS); grants, personal fees, and travel grants from Novartis; and grants from Neracare, Sanofi, and SkylineDx; all outside the submitted work. PG reports personal fees from Roche, MSD, BMS, Boerhinger-Ingelheim, Pfizer, AbbVie, Novartis, Lilly, AstraZeneca, Janssen, Blueprint Medicines, Takeda, Gilead, and ROVI, outside the submitted work. ML acted as a consultant for Roche, AstraZeneca, Lilly, and Novartis, and received honoraria from Theramex, Roche, Novartis, Takeda, Pfizer, Sandoz, and Lilly, outside the submitted work. CBW reports speaker honoraria, travel support, and advisory board: Bayer, BMS, Celgene, Roche, Servier, Shire/Baxalta, RedHil, and Taiho; speaker honoraria from Ipsen; and advisory board in GlaxoSmithKline (GSK), Sirtex, and Rafael; outside the submitted work. JBAGH reports personal fees for advisory role in Neogene Tx; grants and fees paid to institution from BMS, MSD, Novartis, BioNTech, Amgen; and fees paid to institution from Achilles Tx, GSK, Immunocore, Ipsen, Merck Serono, Molecular Partners, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures, Vaximm; outside the submitted work. CH reports being Director of a private company Hardy People Ltd., outside the submitted work. SB reports research grant (institution) from AstraZeneca, Tesaro, and GSK; honoraria from Amgen, AstraZeneca, MSD, GSK, Clovis, Genmab, Merck Serono, Mersana, Pfizer, Seattle Genetics, and Tesaro; outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Advanced breast cancer (aBC) remains incurable and the quest for more effective systemic anticancer agents continues. Promising results have led to the FDA approval of three antibody-drug conjugates (ADCs) and two immune checkpoint inhibitors (ICIs) to date for patients with aBC., Areas Covered: With the anticipated emergence of newer ADCs and ICIs for patients with several subtypes of breast cancer, and given their potential synergy, their use in combination is of clinical interest. In this article, we review the use of ADCs and ICIs in patients with breast cancer, assess the scientific rationale for their combination, and provide an overview of ongoing trials and some early efficacy and safety results of such dual therapy., Expert Opinion: Improvement in the medicinal chemistry of next-generation ADCs, their rational combination with ICIs and other agents, and the development of multiparametric immune biomarkers could help to significantly improve the outlook for patients with refractory aBC.

Background: A systematic review and meta-analysis was performed to estimate mortality in adult patients with solid or hematological malignancies and SARS-CoV-2 infection., Methods: A systematic search of PubMed, up to 31 January 2021, identified publications reporting the case-fatality rate (CFR) among adult patients with solid or hematological malignancies and SARS-CoV-2 infection. The CFR, defined as the rate of death in this population, was assessed with a random effect model; 95% confidence intervals (CI) were calculated., Results: Among 135 selected studies (N = 33,879 patients), the CFR was 25.4% (95% CI 22.9%-28.2%). At a sensitivity analysis including studies with at least 100 patients, the CFR was 21.9% (95% CI 19.1%-25.1%). Among COVID-19 patients with lung (N = 1,135) and breast (N = 1,296) cancers, CFR were 32.4% (95% CI 26.5%-39.6%) and 14.2% (95% CI 9.3%-21.8%), respectively., Conclusions: Patients with solid or hematological malignancies and SARS-CoV-2 infection have a high probability of mortality, with comparatively higher and lower CFRs in patients with lung and breast cancers, respectively., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Multigene signatures (MGS) are used to guide adjuvant chemotherapy (aCT) decisions in patients diagnosed with estrogen receptor (ER)-positive HER2-negative early breast cancer. We used results from three MGS (Oncotype DX® (ODX), MammaPrint® (MP) or Prosigna®) and assessed the concordance between high or low risk of recurrence and the predicted risk of recurrence based on statistical models. In addition, we looked at the impact of MGS results on final aCT administration during the multidisciplinary meeting (MDM). We retrospectively included 129 patients with ER-positive HER2-negative early breast cancer for which MGS testing was performed after MDM at University Hospitals Leuven between May 2013 and April 2019 in case there was doubt about aCT recommendation. Tumor tissue was analyzed either by ODX (N = 44), MP (N = 28), or Prosigna® (N = 57). Eight statistical models were computed: Magee equations (ME), Memorial Sloan Kettering simplified risk score (MSK-SRS), Breast Cancer Recurrence Score Estimator (BCRSE), OncotypeDXCalculator (ODXC), new Adjuvant! Online (nAOL), Mymammaprint.com (MyMP), PREDICT, and SiNK. Concordance, negative percent agreement, and positive percent agreement were calculated. Of 129 cases, 53% were MGS low and 47% MGS high risk. Concordances of 100.0% were observed between risk results obtained by ODX and ME. For MP, BCRSE demonstrated the best concordance, and for Prosigna® the average of ME. Concordances of <50.0% were observed between risk results obtained by ODX and nAOL, ODX and MyMP, ODX and SiNK, MP and MSK-SRS, MP and nAOL, MP and MyMP, MP and SiNK, and Prosigna® and ODXC. Integration of MGS results during MDM resulted in change of aCT recommendation in 47% of patients and a 15% relative and 9% absolute reduction. In conclusion, statistical models, especially ME and BCRSE, can be useful in selecting ER-positive HER2-negative early breast cancer patients who may need MGS testing resulting in enhanced cost-effectiveness and reduced delay in therapeutic decision-making.