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Abstract After disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor, there is no standardized sequence for subsequent treatment lines for estrogen receptor positive (ER+) metastatic breast cancer (MBC). CDK4/6i retrial as a treatment strategy is commonplace in modern clinical practice; however, the available prospective data investigating this strategy have had inconclusive results. To frame this data in a real-world context, we performed a retrospective analysis assessing the efficacy of CDK4/6is in 195 patients who had previous exposure to CDK4/6i in a prior treatment line at our institution. Among patients who had stopped a CDK4/6i due to toxicity, CDK4/6i retrial either immediately after with a different CDK4/6i or in a further treatment line with the same initial CDK4/6i was both safe and effective, with a median time to treatment failure (TTF) of 10.1 months (95%CI, 4.8–16.9). For patients whose disease progressed on a prior CDK4/6i, we demonstrated comparable median TTFs for patients rechallenged with the same CDK4/6i (4.3 months, 95%CI 3.2–5.5) and with a different CDK4/6i (4.7 months, 95%CI 3.7–6.0) when compared to the recent PACE, PALMIRA, and MAINTAIN trials. Exploratory genomic analysis suggested that the presence of mutations known to confer CDK4/6i resistance, such as TP53 mutations, CDK4 amplifications, and RB1 or FAT1 loss of function mutations may be molecular biomarkers predictive of CDK4/6i retrial failure.

Abstract Acquired resistance to PARP inhibitors (PARPi) remains a treatment challenge for BRCA1/2-mutant breast cancer that drastically shortens patient survival. Although several resistance mechanisms have been identified, none have been successfully targeted in the clinic. Using new PARPi-resistance models of Brca1- and Bard1-mutant breast cancer generated in-vivo, we identified FLT1 (VEGFR1) as a driver of resistance. Unlike the known role of VEGF signaling in angiogenesis, we demonstrate a novel, non-canonical role for FLT1 signaling that protects cancer cells from PARPi in-vivo through a combination of cell-intrinsic and cell-extrinsic pathways. We demonstrate that FLT1 blockade suppresses AKT activation, increases tumor infiltration of CD8+ T cells, and causes dramatic regression of PARPi-resistant breast tumors in a T-cell-dependent manner. Moreover, PARPi-resistant tumor cells can be readily re-sensitized to PARPi by targeting Flt1 either genetically (Flt1-suppression) or pharmacologically (axitinib). Importantly, a retrospective series of breast cancer patients treated with PARPi demonstrated shorter progression-free survival in cases with FLT1 activation at pre-treatment. Our study therefore identifies FLT1 as a potential therapeutic target in PARPi-resistant, BRCA1/2-mutant breast cancer.

Abstract Simultaneous presentation of two separate primary breast cancers of differing histology at initial diagnosis is an uncommon phenomenon; it is even rarer to find these pathologically distinct populations within the same biopsy. Here we report the case of a patient diagnosed with clearly demarcated, pathologically heterogenous triple negative breast cancer (TNBC) and HER2+ breast cancer that was treated with a hybrid chemoimmunotherapy regimen combining elements of Keynote-522 and a standard HER2-directed neoadjuvant regimen, yielding apathologic complete response by the time of surgery with no notable adverse events. Molecular analysis of the histologically distinct tumor populations confirmed molecular evidence of differential HER2 expression but also suggested clonal relatedness of the two tumor populations based upon mutational profile, with phenotypic divergence potentially resulting from copy number alterations in NF1. Overall, this case highlights a rare histologic phenomenon that was successfully treated by combining both TNBC and HER2 directed neoadjuvant therapies.

Abstract The KEYNOTE-522 (KN522) regimen for neoadjuvant treatment of triple negative breast cancer (TNBC) utilized q3week dosing for doxorubicin plus cyclophosphamide (AC); however, dose-dense AC (ddAC) has demonstrated superior overall survival (OS) compared to q3week AC in anthracycline and taxane-based regimens. We performed a retrospective analysis assessing the use of ddAC in KN522 and the impact of sequencing ddAC before or after carboplatin/paclitaxel (CbT) plus pembrolizumab on multiple outcomes. 128 patients with TNBC were included. Overall pathologic complete response (pCR) rate of 56%. Sequencing of ddAC vs CbT first showed no difference in pCR rate (ddAC 55% vs. CbT 58%, p = 0.77). However, ddAC first compared to CbT first correlated with a significant increase in the incidence of overall treatment delays (ddAC 70% vs. CbT 51%, p = 0.03), with cytopenias most frequent (ddAC 59% vs. CbT 31%, p = 0.001). ddAC in a modified KN522 regimen is safe, tolerable, and effective. Efficacy is comparable regardless of chemotherapy sequencing, but ddAC first is significantly associated with higher rates of treatment delays and cytopenias.

Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32–1.67]); Black patients (aOR 1.74; 95 CI 1.24–2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70–6.79) and Other (aOR 2.97; 95 CI 1.71–5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83–12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63–3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20–2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66–3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89–22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. Clinical trial number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

PURPOSEBiobanking helps source tissue and blood for studying cancer genomics. Access to biorepository resources in low- and middle-income countries is lacking. Memorial Sloan Kettering Cancer Center (MSK) and the American University of Beirut (AUB) established a joint tissue biorepository at AUB in Beirut, Lebanon. The undertaking encountered key challenges that were unanticipated.MATERIALS AND METHODSPatients age 18 years or older were eligible for enrollment at AUB. After consent, biospecimens were obtained at the time of routine diagnostic and/or therapeutic interventions. Both normal and abnormal tissue and solid and/or liquid specimens were collected from varied body sites. Early on, declining consent was frequently observed, and this was highlighted for investigation to understand potential participants reasoning.RESULTSOf 850 patients approached, 704 (70.8%) elected to consent and 293 (29.5%) declined participation. The number of declined consents led to an amendment permitting the documentation of reasons for same. Of 100 potential participants who declined to consent and to whom outreach was undertaken, 63% indicated lack of research awareness and 27% deferral to their primary physician or family member. A financial gain for AUB was cited as concern by 5%, cultural boundaries in 4%, and 1% expressed concern about confidentiality. Of the patients who elected to consent, 682 biospecimens were procured.CONCLUSIONThe AUB-MSK biospecimen repository has provided a unique resource for interrogation. Patient participation rate was high, and analyses of those who elected not to consent (29%) provide important insights into educational need and the local and cultural awareness and norms.

Abstract Background Genetic testing (GT) for hereditary cancer predisposition is traditionally performed on selected genes based on established guidelines for each cancer type. Recently, expanded GT (eGT) using large hereditary cancer gene panels uncovered hereditary predisposition in a greater proportion of patients than previously anticipated. We sought to define the diagnostic yield of eGT and its clinical relevance in a broad cancer patient population over a 5-year period. Methods A total of 17,523 cancer patients with a broad range of solid tumors, who received eGT at Memorial Sloan Kettering Cancer Center between July 2015 to April 2020, were included in the study. The patients were unselected for current GT criteria such as cancer type, age of onset, and/or family history of disease. The diagnostic yield of eGT was determined for each cancer type. For 9187 patients with five common cancer types frequently interrogated for hereditary predisposition (breast, colorectal, ovarian, pancreatic, and prostate cancer), the rate of pathogenic/likely pathogenic (P/LP) variants in genes that have been associated with each cancer type was analyzed. The clinical implications of additional findings in genes not known to be associated with a patients’ cancer type were investigated. Results 16.7% of patients in a broad cancer cohort had P/LP variants in hereditary cancer predisposition genes identified by eGT. The diagnostic yield of eGT in patients with breast, colorectal, ovarian, pancreatic, and prostate cancer was 17.5%, 15.3%, 24.2%, 19.4%, and 15.9%, respectively. Additionally, 8% of the patients with five common cancers had P/LP variants in genes not known to be associated with the patient’s current cancer type, with 0.8% of them having such a variant that confers a high risk for another cancer type. Analysis of clinical and family histories revealed that 74% of patients with variants in genes not associated with their current cancer type but which conferred a high risk for another cancer did not meet the current GT criteria for the genes harboring these variants. One or more variants of uncertain significance were identified in 57% of the patients. Conclusions Compared to targeted testing approaches, eGT can increase the yield of detection of hereditary cancer predisposition in patients with a range of tumors, allowing opportunities for enhanced surveillance and intervention. The benefits of performing eGT should be weighed against the added number of VUSs identified with this approach.

Abstract Pathogenic germline mutations in the RAD51 paralog genes RAD51C and RAD51D, are known to confer susceptibility to ovarian and triple-negative breast cancer. Here, we investigated whether germline loss-of-function variants affecting another RAD51 paralog gene, RAD51B, are also associated with breast and ovarian cancer. Among 3422 consecutively accrued breast and ovarian cancer patients consented to tumor/germline sequencing, the observed carrier frequency of loss-of-function germline RAD51B variants was significantly higher than control cases from the gnomAD population database (0.26% vs 0.09%), with an odds ratio of 2.69 (95% CI: 1.4–5.3). Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.

Abstract Purpose We examined the characteristics of breast cancer patients with oligometastases (OM) treated with stereotactic ablative body radiotherapy (SABR) to identify factors associated with local progression, distant metastasis progression, time to subsequent therapy, progression‐free survival (PFS), and overall survival (OS). Methods We retrospectively reviewed a single‐institution database of patients treated with radiotherapy between 2008 and 2018 and identified 79 patients who received SABR to OM. Twenty‐seven patients had genetic testing of metastatic tumors using an institutional targeted sequencing platform. Kaplan–Meier analysis, Cox regression, and competing risk models were used to compare clinical and genetic correlates with outcomes. Results Median follow‐up was 50 months (IQR: 29–66) with 67% of patients alive at the last follow‐up. Of the 65% of patients who progressed, 82% progressed outside of the radiation field, 18% experienced local failure, and 80% had oligoprogression. Median OS was 86 months (IQR: 29–66), and PFS was 33 months (IQR: 10–38). Less than 5 years from diagnosis to SABR and triple‐negative breast cancer (TNBC) were associated with worse OS. Advanced T stage, any prior chemotherapy, and TNBC were associated with worse PFS. Alterations in CEBPB, RB1, TBX3, PTEN, and CDK4 were associated with worse survival outcomes. Conclusion Long‐term systemic disease control and survival can be achieved with SABR for oligometastatic breast cancer. Hormone receptor‐positive patients with a long disease interval from initial diagnosis and limited systemic progression history may be ideal for SABR to all sites of disease.

Abstract Metaplastic breast carcinoma (MpBC) is a rare special histologic subtype of breast carcinoma characterized by the presence of squamous and/or mesenchymal differentiation. Most MpBCs are of triple-negative phenotype and neoadjuvant chemotherapy (NAC) is frequently utilized in patients with MpBC. The aim of this study was to evaluate response to NAC in a retrospective cohort of MpBCs. We identified 44 patients with MpBC treated with NAC at our center between 2002 and 2018. Median age was 48 years, 86% were clinical stage II–III, and 36% were clinically node-positive. Most (80%) MpBCs were triple-negative or low (1–10%) hormonal receptor positive and HER2 negative on pre-NAC biopsy. While on NAC, 49% showed no clinical response or clinico-radiological progression. Matrix-producing subtype was associated with clinico-radiological response (p = 0.0036). Post NAC, two patients initially ineligible for breast-conserving surgery (BCS) were downstaged to be eligible for BCS, whereas three patients potentially eligible for BCS before treatment became ineligible due to disease progression. Only one (2%) patient had a pathologic complete response (pCR). Among the 16 patients presenting with biopsy-proven clinical node-positive disease, 3 (19%) had nodal pCR. Axillary lymph node dissection was avoided in 3 (19%) patients who had successful axillary downstaging. Residual cancer burden (RCB) was assessed in 22 patients and was significantly associated with disease-free survival and overall survival. We observed a poor response or even disease progression on NAC among patients with MpBC, suggesting that NAC should be reserved for patients with inoperable MpBC.

Abstract Human biomarkers were used to evaluate the lead (Pb) and arsenic (As) exposure of local people who lived in an agricultural area with intense agrochemical usage and who consumed groundwater. Although the heavy metals/metalloids in the groundwater were at low concentrations, they could cause adverse effects due to a high daily water intake rate over the long term. Biomarkers (hair, fingernails and urine) were collected from 100 subjects along with the local shallow groundwater and tap water, which is the treated deep groundwater, and investigated for the concentrations of As and Pb. Shallow groundwater had an average pH of 5.21 ± 1.90, ranging from 3.77 to 8.34, with average concentrations of As and Pb of 1.311 µg/L and 6.882 µg/L, respectively. Tap water had an average pH of 5.24 ± 1.63, ranging from 3.86 to 8.89, with the average concentrations of As and Pb of 0.77 µg/L and 0.004 µg/L, respectively. The levels of both As and Pb in the hair, fingernails and urine of shallow groundwater-consuming residents were greater than those in the hair, fingernails and urine of tap water-consuming residents. Interestingly, the As level in urine showed a linear relationship with the As concentration in groundwater (R2 = 0.91). The average water consumption rate was approximately two-fold higher than the standard; thus, its consumption posed a health risk even at the low As and Pb levels in the groundwater. The hazard index (HI) ranged from 0.01 to 16.34 (average of 1.20 ± 2.50), which was higher than the acceptable level. Finally, the concomitant factors for As and Pb in the urine, hair and nails from both binary logistic regression and odds ratio (OR) analysis indicated that groundwater consumption was the major concomitant risk factor. This study suggested that direct consumption of this groundwater should be avoided and that the groundwater should be treated, especially before consumption. In conclusion, urine is suggested to be a biomarker of daily exposure to As and Pb, while for long-term exposure to these metals, fingernails are suggested as a better biomarker than hair.

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

BackgroundPatient experience when transitioning home from hospital is an important quality metric linked to improved patient outcomes. We evaluated the impact of a hospital-based care transition intervention, patient-oriented discharge summary (PODS), on patient experience across Ontario acute care hospitals.MethodsWe used a repeated cross-sectional study design to compare yearly positive (top-box) responses to four questions centered on discharge communication from the Canadian Patient Experience Survey (2016-2020) among three hospital cohorts with various levels of PODS implementation. Generalized Estimating Equations using a binomial likelihood accounting for site level clustering was used to assess continuous linear time trends among cohorts and cohort differences during the post-implementation period. This research had oversight from a public advisory group of patient and caregiver partners from across the province.Results512,288 individual responses were included. Compared to non-implementation hospitals, hospitals with full implementation (>50% discharges) reported higher odds for having discussed the help needed when leaving hospital (OR = 1.18, 95% CI = 1.02-1.37) and having received information in writing about what symptoms to look out for (OR = 1.44, 95% = 1.17-1.78) post-implementation. The linear time trend was also significant when comparing hospitals with full versus no implementation for having received information in writing about what symptoms to look out for (OR = 1.05, 95% CI = 1.01-1.09).InterpretationPODS implementation was associated with higher odds of positive patient experience, particularly for questions focused on discharge planning. Further efforts should center on discharge management, specifically: understanding of medications and what to do if worried once home.

Purpose - Children living in agricultural areas are exposed to pesticides in their living areas and through activities of daily living. These exposures may lead to adverse health effects. The purpose of this paper is to investigate household environmental and behavioural factors associated with chlorpyrifos exposure and resultant adverse health effects in children living in an agricultural community. Design/methodology/approach - A cross-sectional study was conducted including 65 toddlers (age of 12–36 months) and their parents were face-to-face interviewed from January to February 2016. Toddler’s hands and feet, toys and floors were wiped for chlorpyrifos residue analysis. The wipes were extracted and analysed by gas chromatography with a flame photometric detector, and blood cholinesterase activity was measured by the EQM Test-mate (model 400). Findings - The average age (± standard deviation) of children was 19.9 (±5.9) months. Chlorpyrifos detections were 61.5 per cent (hands), 57.1 per cent (toys), 53.8 per cent (floors) and 30.8 per cent (feet). The highest chlorpyrifos residue concentration was detected on toy surface (3.022 µg/m2). Chlorpyrifos residues on hands and feet were positively correlated with concentrations on floors and toys (Spearman’s ρ, p

Automotive manufacturing is one of the potential sources of air pollution particularly involving volatile organic compounds (VOCs). This study intensively evaluated VOC emissions and their dispersion from the industry. The measured VOCs were speciated for further evaluation of their odor threats according to the characteristics of each compound. Mathematical emission and air dispersion models were applied to assist in elaborating the source–receptor relationship allowing the determining of existing business-as-usual conditions with proposed mitigation measures to manage the pollution of the factory studied in this paper. Seven VOC species potentially caused odor problems to the surrounding community, including 1-butanol, ethyl benzene, toluene, m,p xylene, o xylene, methyl ethyl ketone, and methyl isobutyl ketone. The results from the AERMOD dispersion model revealed that the smell from these chemicals could reach up to about 800 m from the source. Analysis of mitigation measures indicated that two interesting scenarios should be considered according to their effectiveness. The concentrations of VOCs can decrease by up to 4.7, 14.0 and 24.9% from increasing the physical stack height by +1, +3 and +5 m from its existing height, respectively. Modification of the aeration tank of the wastewater treatment unit to a closed system also helped to reduce about 27.8% of emissions resulting in about a 27.6% decreased ambient air concentration. This study provided useful information on the characteristics of VOCs emitted by the automobile manufacturing industry. It also demonstrated the relevant procedures and highlights the necessity to comprehensively analyze the source–receptor relationship to evaluate the most appropriate measures in managing industrial air pollution.

Purpose - Dust (particulate matters) is very dangerous to our health as it is not visible with our naked eyes. Emissions of dust concentrations in the natural environment can occur mainly by road traffic, constructions and dust generating working environments. The purpose of this paper is to assess the ambient dust pollution status and to find out the association between PM concentrations and other determinant factors such as wind speed, ambient temperature, relative humidity and traffic congestion. Design/methodology/approach - A cross-sectional study was conducted for two consecutive months (June and July, 2016) at a residential site (Defence Services Liver Hospital, Mingaladon) and a commercial site (Htouk-kyant Junction, Mingaladon) based on WHO Air Quality Reference Guideline Value (24-hour average). Hourly monitoring of PM2.5 and PM10 concentration and determinant factors such as traffic congestion, wind speed, ambient temperature and relative humidity for 24 hours a day was performed in both study sites. CW-HAT200 handheld particulate matters monitoring device was used to assess PM concentrations, temperature and humidity while traffic congestion was monitored by CCTV cameras. Findings - The baseline PM2.5 and PM10 concentrations of Mingaladon area were (28.50±11.49)µg/m3 and (52.69±23.53)µg/m3, means 61.48 percent of PM2.5 concentration and 54.92 percent of PM10 concentration exceeded than the WHO reference value during the study period. PM concentration usually reached a peak during early morning (within 3:00 a.m.-5:00 a.m.) and at night (after 9:00 p.m.). PM2.5 concentration mainly depends on traffic congestion and temperature (adjusted R2=0.286), while PM10 concentration depends on traffic congestion and relative humidity (adjusted R2=0.292). Wind speed played a negative role in both PM2.5 and PM10 concentration with r=−0.228 and r=−0.266. Originality/value - The air quality of the study area did not reach the satisfiable condition. The main cause of increased dust pollution in the whole study area was high traffic congestion (R2=0.63 and 0.60 for PM2.5 and PM10 concentration).

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4