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Purpose: Vulvar squamous cell carcinoma (VSCC), a rare gynecologic malignancy, has been rising in incidence. Molecular classification on the basis of human papilloma virus (HPV) and tumor protein 53 (p53) status has identified three clinically distinct subtypes, but we still treat all VSCCs the same. Here, we review molecular classification of VSCC, outline treatment landscape, and highlight potential for targeted therapies in advanced VSCC., Design: We conducted a comprehensive review of the literature on treatment of advanced VSCC with particular focus on the implications of molecular stratification on the basis of HPV and p53 status on the treatment landscape of advanced VSCC., Results: Incorporation of HPV and p53 status in locoregional treatment decision making has the potential to advise (de)escalation strategies. The role of immunotherapy, alone and in combination, requires further exploration particularly earlier in the course of the disease. In advanced stages, potential for targeted therapies in VSCCs include inhibitors of vascular endothelial growth factor, endothelial growth factor receptor, cell cycle, and DNA damage response, particularly in HPV-negative (HPV-) VSCCs. Targeting the phosphoinositide 3 kinase/mammalian target of rapamycin pathway is attractive in HPV-positive and HPV-/p53 wildtype VSCCs. Trials incorporating antibody-drug conjugates (eg, trophoblast cell-surface antigen 2, human epidermal growth factor receptor 2) should be considered, and basket trials in perineal squamous cell cancers are warranted. Preclinical models are limited and should be expanded to inform trial design., Conclusion: Like other rare cancers, vulvar cancer lags behind in the identification and optimization of precision medicine strategies. Molecular-based preclinical models and rationally designed clinical trials, incorporating high-quality translational studies, are urgently required. These trials will require international collaboration to ensure feasibility and improvement of outcomes for women diagnosed with this disease.

Purpose: In patients with oligometastatic disease (OMD) treated with stereotactic body radiation therapy (SBRT), those who develop brain metastases (BrM) may have poor outcomes. We aimed to investigate variables associated with BrM development in this population., Methods: Patients with ≤ 5 extracranial metastases from solid tumors treated with SBRT from 2008 to 2016 at Sunnybrook Odette Cancer Centre were included. We investigated the association between covariates and CIBrM (cumulative incidence of BrM) using Fine-Gray analysis, and progression-free survival (PFS) and overall survival (OS) using Cox regression. We investigated the association between extracranial progression and CIBrM using time-based conditional analysis., Results: Among 404 patients, the most common primary sites were lung, colorectal, prostate, breast and kidney. Median follow-up was 49 months. Median PFS was 25 months. Median OS was 70 months. 58 patients developed BrM, and 5-year CIBrM was 16%. On multivariable analysis, number of extracranial metastases, location of metastases, total planning target volume (PTV), and time from primary diagnosis to OMD were not associated with CIBrM, although several of these variables were associated with extracranial PFS and OS. Primary site was associated with CIBrM, with colorectal and prostate cancer associated with lower CIBrM compared to lung cancer. Widespread extracranial progression (≥ 5 sites) within 24, 36, 48 and 60 months of OMD diagnosis was independently associated with higher CIBrM., Conclusion: In patients with OMD treated with SBRT, baseline variables related to extracranial disease burden and distribution were not associated with BrM development, while primary site and widespread extracranial progression were associated with BrM development., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking., Objective: To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer., Design, Setting, and Participants: This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022., Main Outcomes and Measures: Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses., Results: Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively., Conclusions and Relevance: In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

Purpose: Ductal carcinoma in situ (DCIS) is routinely treated with adjuvant radiotherapy (RT) after breast-conserving surgery (BCS). The inability to accurately estimate an individual's risk of local recurrence (LR) and invasive LR using clinicopathologic factors (CPF) contributes to the overtreatment of DCIS. We examined the impact of the 12-gene DCIS Score (DS) and the 21-gene Recurrence Score (RS) on the accuracy of predicting LR and invasive LR., Methods: A population-based cohort diagnosed with pure DCIS treated with BCS ± RT from 1994 to 2003 was used. All patients had expert pathology review and assessment of the DS and RS. Predictive models (CPF alone, DS + CPF, and RS + CPF) were developed using multivariable Cox regression analyses to predict 10-year LR and invasive LR risks. Models were evaluated on the basis of c-statistic, -2log likelihood estimate (-2LLE), and Akaike information criterion. Calibration was performed using bootstrap resamples, with replacement., Results: The cohort includes 1,226 women treated with BCS; 712 received RT. 194 women (15.8%) experienced ipsilateral LR as a first event; 112 were invasive. Models including the DS or RS performed better in predicting the 10-year risk of LR compared with models on the basis of CPF alone with excellent calibration. The two molecular-based models also performed better in predicting invasive LR compared with the CPF model but the model incorporating the RS did not perform better in the prediction of invasive LR compared with the DS-based model., Conclusion: Models incorporating the DS or RS more accurately predicted the 10-year risk of LR and invasive LR after BCS compared with models on the basis of CPF alone. Inclusion of the RS, compared with DS, did not improve the prediction of the 10-year risk of invasive LR.

Background: Invadopodia facilitate cancer cell extravasation, but the molecular mechanism whereby invadopodia-specific proteases such as MT1-MMP are called to invadopodia is unclear., Methods: Mass spectrometry and immunoprecipitation were used to identify interactors of MT1-MMP in metastatic breast cancer cells. After identification, siRNA and small molecule inhibitors were used to assess the effect these interactors had on cellular invasiveness. The chicken embryo chorioallantoic membrane (CAM) model was used to assess extravasation and invadopodia formation in vivo., Results: In metastatic breast cancer cells, MT1-MMP was found to associate with plectin, a cytolinker and scaffolding protein. Complex formation between plectin and MT1-MMP launches invadopodia formation, a subtype we termed i plectin ( i  = invadopodial). i Plectin delivers MT1-MMP to invadopodia and is indispensable for regulating cell surface levels of the enzyme. Genetic depletion of plectin with siRNA reduced invadopodia formation and cell invasion in vitro. In vivo extravasation efficiency assays and intravital imaging revealed i plectin to be a key contributor to invadopodia ultrastructure and essential for extravasation. Pharmacologic inhibition of plectin using the small molecule Plecstatin-1 (PST-1) abrogated MT1-MMP delivery to invadopodia and extravasation efficiency., Conclusions: Anti-metastasis therapeutic approaches that target invadopodia are possible by disrupting interactions between MT1-MMP and i plectin., Clinical Trial Registration Number: NCT04608357., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: This study aimed to examine the impact of the level of HER2 overexpression on pathologic and clinical outcomes in HER2-positive breast cancer (BC) patients treated with neoadjuvant therapy (NAT)., Methods: Women with Stage II or III HER2-positive BC who received anthracycline-taxane-trastuzumab NAT regimens followed by curative-intent surgery were included. Patients were classified according to tumor HER2 expression into HER2-high (immunohistochemistry (IHC) 3+ or fluorescence in situ hybridization (FISH) HER2/CEP17 ratio ≥5 or HER2 copy number ≥10) and HER2-intermediate (IHC 2+ with HER2/CEP17 ratio ≥2 to <5 or copy number ≥4 to <10). Univariate and multivariate logistic regression analyses were performed using HER2 expression as a categorical variable. The primary outcome was pathological complete response (pCR). Estimated 3-year disease-free survival (DFS) and Overall Survival (OS) were secondary outcomes., Results: Among 161 patients with HER2-positive BC, 139 (86%) and 22 (14%) were classified as HER2-high and HER2-intermediate, respectively; 105 (65.2%) had hormone receptor (HR)-positive tumors; 72 (45%) achieved a pCR. In the overall population, pCR rates of 18% and 49% were achieved in HER2-intermediate and HER2-high cases, respectively (odds ratio [OR] = 0.23 95% CI 0.07-0.72; P = .007). No pCRs were observed among HR-positive, HER2-intermediate cases. Estimated 3-year DFS was 97.1% versus 89.3% for patients achieving a pCR versus those with residual disease, respectively (P = .0011)., Conclusion: We found that patients with HER2-high disease were more likely to achieve pCR after NAT compared to patients with HER2-intermediate BC, a subgroup of patients that may benefit from more personalized NAT strategies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite consensus guidelines, most patients with early-stage triple-negative (TN) and HER2-positive (HER2+) breast cancer do not see a medical oncologist prior to surgery and do not receive neoadjuvant chemotherapy (NAC). To understand barriers to care, we aimed to characterize the relationship between geography (region of residence and cancer centre proximity) and receipt of a pre-treatment medical oncology consultation and NAC for patients with TN and HER2+ breast cancer. Using linked administrative datasets in Ontario, Canada, we performed a retrospective population-based analysis of women diagnosed with stage I-III TN or HER2+ breast cancer from 2012 to 2020. The outcomes were a pre-treatment medical oncology consultation and the initiation of NAC. We created choropleth maps to assess the distribution of the outcomes and cancer centres across census divisions. To assess the relationship between distance to the nearest cancer centre and outcomes, we performed multivariable regression analyses adjusted for relevant factors, including tumour extent and nodal status. Of 14,647 patients, 29.9% received a pre-treatment medical oncology consultation and 77.7% received NAC. Mapping demonstrated high interregional variability, ranging across census divisions from 12.5% to 64.3% for medical oncology consultation and from 8.8% to 64.3% for NAC. In the full cohort, compared to a distance of ≤5 km from the nearest cancer centre, only 10-25 km was significantly associated with lower odds of NAC (OR 0.83, 95% CI 0.70-0.99). Greater distances were not associated with pre-treatment medical oncology consultation. The interregional variability in medical oncology consultation and NAC for patients with TN and HER2+ breast cancer suggests that regional and/or provider practice patterns underlie discrepancies in the referral for and receipt of NAC. These findings can inform interventions to improve equitable access to NAC for eligible patients.

Background: Breast cancer (BC) is the second most common etiology of brain metastases (BrM). We aimed to examine the incidence of BrM among all BC patients presenting to a large tertiary cancer centre over one decade., Methods: We included all BC patients presenting consecutively between 2009 and 2019 and cross referenced that cohort to a radiotherapy database, identifying patients treated for BrM at any time following their initial presentation. Cumulative incidences (CI) of BrM diagnoses were calculated using death as a competing risk and compared using the Fine-Gray method. Overall survival was estimated using the Kaplan Meier method., Results: We identified 12,995 unique patients. The CI of BrM in patients who initially presented with Stage 0-4 disease was 2.1%, 3.7%, 9.4%, 10.6%, and 28.7%, respectively at 10 years. For 8,951 patients with available molecular subtype data, 6,470 (72%), 961 (11%), 1,023 (11%), and 497 (6%) had hormone-receptor (HR)-positive/ERBB2-, HR-negative/ERBB2-, HR-positive/ERBB2 + , and HR-negative/ERBB2 + disease, respectively; the CI of BrM in each was 7.6%, 25.3%, 24.1%, and 26.6%, at 10 years following BC diagnosis, respectively. Median overall survival (OS) following BC diagnosis and BrM diagnosis was 28 years 95% CI [25, 32] and 10 months 95% CI [9, 12], respectively., Conclusions: From a large, registry-based study, we observed that patients with ERBB2 + and triple negative BC have the highest incidence of BrM. Our data supports prospective surveillance brain MRI studies. Given advancements in BrM treatment, clinicians should have a low threshold for brain imaging in BC patients with high risk subtypes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Managing breast cancer in premenopausal women poses unique challenges due to its considerable effect on both morbidity and mortality. Goserelin, a gonadotropin-releasing hormone agonist, has emerged among the various modalities as a preferred option for ovarian function suppression, owing to its efficacy in reducing ovarian estrogen production in premenopausal women with hormone receptor-positive breast cancer. Recent studies have affirmed the efficacy and safety of long-acting (LA) goserelin 10.8 mg every 12 weeks, offering comparable outcomes to monthly injections. This flexibility enables personalized treatment approaches, potentially enhancing patient satisfaction. Off-label utilization of goserelin LA surged during the coronavirus disease pandemic, prompting initiatives to broaden its use for breast cancer treatment. Switching to goserelin LA can streamline treatment, boost adherence, and optimize resource utilization. With the recent approval of goserelin 10.8 mg LA by Health Canada on 6 May 2024, for use in breast cancer, Canada is the latest to join over 60 countries worldwide to expand the accepted indications for goserelin LA and ensure its availability to potentially enhance healthcare delivery, patient care, and breast cancer outcomes. Goserelin LA offers premenopausal patients a means to more effectively manage the constraints imposed by breast cancer treatment and its impact on survivorship.

Background: Breast cancer (BC) is frequently diagnosed among Canadian women. While targeted therapies are available for most BC patients; treatment resistance is common and novel therapeutic targets are of interest. Thyroid hormones (TH) bound to thyroid hormone receptors (THR) influence cell proliferation and differentiation; they are also involved in the growth and development of normal breast tissue. Evidence suggests that THRβ is a tumor suppressor in various solid tumors., Purpose: This narrative review discusses retrospective studies regarding the clinical relevance of THRβ as a potential prognostic biomarker and therapeutic target in BC., Methods: We consulted with an information specialist to develop a search strategy to find all literature related to THRα expression as a potential prognostic and therapeutic biomarker in breast cancer. The primary search was developed for Medline and translated to Embase. The searches were conducted on the Ovid platform on 18 August 2023., Results: Across seven retrospective studies identified, several have shown an association between higher THRβ1 expression with a lower risk of BC recurrence and with longer overall survival., Conclusions: Some evidence suggests that THRβ expression is associated with a lower risk of BC recurrence and death. Validation of THRβ as an independent prognostic biomarker and possible predictive biomarker of response to endocrine therapy and/or chemotherapy is of interest. Given that THRβ is upstream of the AKT/PI3K pathway, its potential as a predictive biomarker of response to AKT inhibitors and/or PI3K inhibitors may also be of value. Finally, the potential re-purposing of THRβ agonists as anti-cancer agents warrants investigation.

Chemotherapy-induced nausea and vomiting (CINV) is a common toxicity that may impair the quality of life of patients with various malignancies ranging from early to end stages. In light of frequent changes to the guidelines for optimal management of CINV, we undertook this narrative review to compare the most recent guidelines published by ASCO (2020), NCCN (2023), MASCC/ESMO (2023), and CCO (2019). The processes undertaken by each organization to evaluate existing literature were also described. Although ASCO, NCCN, MASCC/ESMO, and CCO guidelines for the treatment and prevention of CINV share many fundamental similarities, the literature surrounding low and minimal emetic risk regimens is lacking. Current data regarding adherence to these guidelines is poor and warrants further investigation to improve care., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Trastuzumab deruxtecan is a new treatment option for patients with advanced human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC). Although HER2-low status has been characterized in early and advanced BC, it has yet to be fully characterized in brain metastases (BrM)., Methods: Patients who underwent surgery for BC BrM at Sunnybrook Health Sciences Centre and for whom HER2 status was available on resected BrM were studied. Estrogen receptor, progesterone receptor, and HER2 status were assessed on the basis of ASCO/College of American Pathologists (CAP) guidelines. HER2-zero was defined as immunohistochemistry (IHC) 0; HER2-low was defined as IHC 1+ or IHC 2+ with fluorescence in situ hybridization (FISH)-negative status. HER2-positive (HER2+) was defined as IHC 3+ or IHC 2+ with positive FISH. Clinicopathologic features were recorded. We also assessed the prognostic association between extent of HER2 expression and (1) brain-specific progression-free survival (bsPFS), as well as (2) overall survival (OS)., Results: In this retrospective cohort of 102 patients with resected BC BrM, 53% (n = 54) were HER2+, 29.4% (n = 30) were HER2-low, and 17.6% (n = 18) had HER2-zero status. Among BrM that were triple-negative on the basis of ASCO/CAP guidelines, 63.6% (n = 14/22) were reclassified as being HER2-low. Sixty percent (n = 15/25) of BrM that were hormone receptor-positive/HER2-negative (HR+/HER2-) were reclassified as being HER2-low. In total, 51 patients had matched primary breast and BrM tissue available; results of HER2 status when categorized as HER2-zero, HER2-low, and HER2+ were concordant in 82.3% (n = 42/51) of cases (Cohen's kappa, 0.58; P = .07). There was no significant association between HER2-zero, HER2-low, and HER2+ status in BrM and either bsPFS or OS., Conclusion: Among patients with surgically resected BrM, a high proportion of those with metastatic triple-negative BC and HR+/HER2- disease have HER2-low BrM with potential to benefit from HER2-targeted therapy.

Introduction: Women with metastatic breast cancer (BC) are at risk of developing brain metastases (BrM), which may result in significant morbidity and mortality. Given the emergence of systemic therapies with activity in the brain, more breast oncology clinical trials include patients with BrM, but most require extracranial disease progression for trial participation., Methods: We evaluated the proportion of patients with BC BrM who have intracranial disease progression in the setting of stable extracranial disease in a retrospective cohort study of 751 patients treated between 2008 and 2018 at the Sunnybrook Odette Cancer. Extracranial disease progression was defined as any progression outside of the brain within 4 weeks of a patient's local/regional treatment. Clinical/pathologic characteristics and outcomes were also abstracted from patients' medical records., Results: Of 752 patients in the cohort, 691 were included in our study. Sixty-one patients were excluded due to the presence of a second primary tumor or uncertain tissue origin of the BrM. BC subtype based on the primary tumor was known for 592 (85.6%) patients; 33.1% (n = 196) had HER2+ disease, 40% (n = 237) had HR+/HER2- disease, and 26.9% (n = 159) had triple negative BC. Extracranial disease status was available for 677 patients (98%); 41.1% (n = 284/691) had stable extracranial disease and 56.8% (n = 393/691) had extracranial disease progression within 4 weeks of treatment for BrM., Discussion: A high proportion of patients with BC BrM (41.1%) would be excluded from clinical trials due to stable extracranial disease. Efforts should be made to design trials for this patient population., Competing Interests: Disclosure KJJ is a speaker/advisor board/consultant for Amgen, Apo Biologix, AstraZeneca, Daiichi Sankyo, Eli Lilly, Esai, Genomic Health, Knight Therapeutics, Pfizer, Roche, Merck, Novartis, Seagen. KJJ received research funding from: Eli Lilly, AstraZeneca, Seagen. SD is an advisor/consultant for AbbVie, Xpan Medical, Synaptive, Omniscient. SD is also a board member in Subcortical Surgery Group and provided past educational seminars: AbbVie, Subcortical Surgery Group, Congress of Neurological Surgeons, American Association of Neurological Surgeons, Society for NeuroOncology. SD received research grants from Alkerme, Medicenna and received travel accommodations/expenses from Subcortical Surgery Group, Congress of Neurological Surgeons, American Association of Neurological Surgeons, Society for NeuroOncology, Integra. AS is an advisor/consultant for AbbVie, Merck, Roche, Varian (Medical Advisory Group), Elekta (Gamma Knife Icon), BrainLAB, and VieCure (Medical Advisory Board). AS is a board member in International Stereotactic Radiosurgery Society (ISRS) and is a co-chair in AO Spine Knowledge Forum Tumor. AS also provided educational seminars in Elekta AB, Accuray Inc., Varian (CNS Teaching Faculty), BrainLAB, Medtronic Kyphon; received research grant from Elekta AB; received travel accommodations/expenses: Elekta, Varian, BrainLAB. AS also belongs to the Elekta MR Linac Research Consortium, Elekta Spine, Oligometastases and Linac Based SRS Consortia., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Clinical data supporting the best therapeutic approach in leptomeningeal disease (LMD; also known as leptomeningeal metastases or leptomeningeal carcinomatosis) are lacking. Despite the development of new agents and increasing incidence of central nervous system metastases, patients with LMD are often excluded from clinical trials in breast cancer, with very few conducted specifically in LMD. Consequently, current evidence may not provide an accurate reflection of real-world clinical practice. This review aims to provide further insight into the treatment strategies for patients with breast cancer and LMD. We explore differences between clinical and real-world studies, considering inclusion criteria, levels of evidence for LMD diagnosis, and time between diagnosis of LMD and LMD-specific treatment initiation. Patient prognosis is poor; median overall survival is limited to several months, with approximately 10% of patients alive at 12 months. Efficacy results have been reported for various systemic and intrathecal agents in LMD to date. Systemic therapies under investigation for LMD in breast cancer include tucatinib, trastuzumab deruxtecan, and paclitaxel trevatide; trastuzumab is the main intrathecal agent currently under investigation. Recent trials investigating systemic or intrathecal therapies are typically small, single-arm studies, and most are restricted to patients with human epidermal growth factor receptor 2-positive breast cancer. Moreover, the variability among inclusion criteria and response assessment tools makes the interpretation of results difficult. Large retrospective cohorts with various inclusion criteria and treatment regimens provide some real-world data. However, there remains an urgent need for randomised clinical trials which include patients with LMD across all breast cancer subtypes., Competing Interests: Declaration of competing interest Rupert Bartsch reports advisory roles at AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Grunenthal, MSD, Novartis, Pfizer, Pierre Fabre, Roche, and Seagen; lecture honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Grunenthal, MSD, Novartis, Pfizer, Pierre Fabre, Roche, and Seagen; and research support from Daiichi Sankyo. Katarzyna Jerzak reports speaker/consultant/advisory roles at Amgen, Astra Zeneca, Apo Biologix, Eli Lilly, Eisai, Exact Sciences, Knight Therapeutics, Pfizer, Merck, Myriad Genetics, Novartis, Purdue Pharma, Roche, Seagen, and Viatris; research funding from Eli Lilly, Astra Zeneca, and Seagen; and has a patent regarding the use of dronedarone and related derivatives as anticancer agents. Louis Larrouquere reports research grants from Seagen and consultant fees from AstraZeneca. Volkmar Müller reports speaker honoraria from AstraZeneca, Daiichi-Sankyo, Eisai, Gilead, high5 Oncology, Medac, Medscape, MSD, Novartis, Onkowissen, Pfizer, Pierre Fabre, Roche, and Seagen; consultancy honoraria from Amgen, ClinSol, Daiichi-Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Roche, Sanofi, Seagen, and Stemline; institutional research support from AstraZeneca, Genentech, Novartis, Roche, and Seagen; and travel grants from AstraZeneca, Daiichi-Sankyo, Gilead, Pfizer, and Roche. Emilie Le Rhun reports a research grant from BMS and honoraria for lectures or advisory boards from AstraZeneca, Bayer, Janssen, Leo Pharma, Pierre Fabre, Roche, Seagen, and Servier., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Patients with postpartum breast cancer diagnosed after cessation of breastfeeding (postweaning, PP-BCPW) have a particularly poor prognosis compared with patients diagnosed during lactation (PP-BCDL), or to pregnant (Pr-BC) and nulliparous (NP-BC) patients, regardless of standard prognostic characteristics. Animal studies point to a role of the involution process in stimulation of tumor growth in the mammary gland. However, in women, the molecular mechanisms that underlie this poor prognosis of patients with PP-BCPW remain vastly underexplored, due to of lack of adequate patient numbers and outcome data., Experimental Design: We explored whether distinct prognostic features, common to all breast cancer molecular subtypes, exist in postpartum tumor tissue. Using detailed breastfeeding data, we delineated the postweaning period in PP-BC as a surrogate for mammary gland involution and performed whole transcriptome sequencing, immunohistochemical, and (multiplex) immunofluorescent analyses on tumor tissue of patients with PP-BCPW, PP-BCDL, Pr-BC, and NP-BC., Results: We found that patients with PP-BCPW having a low expression level of an immunoglobulin gene signature, but high infiltration of plasma B cells, have an increased risk for metastasis and death. Although PP-BCPW tumor tissue was also characterized by an increase in CD8+ cytotoxic T cells and reduced distance among these cell types, these parameters were not associated with differential clinical outcomes among groups., Conclusions: These data point to the importance of plasma B cells in the postweaning mammary tumor microenvironment regarding the poor prognosis of PP-BCPW patients. Future prospective and in-depth research needs to further explore the role of B-cell immunobiology in this specific group of young patients with breast cancer., (©2023 The Authors; Published by the American Association for Cancer Research.)

Up to 30% of breast cancer (BC) patients will develop distant metastases (DM), for which there is no cure. Here, statistical and machine learning (ML) models were developed to estimate the risk of site-specific DM following local-regional therapy. This retrospective study cohort included 175 patients diagnosed with invasive BC who later developed DM. Clinicopathological information was collected for analysis. Outcome variables were the first site of metastasis (brain, bone or visceral) and the time interval (months) to developing DM. Multivariate statistical analysis and ML-based multivariable gradient boosting machines identified factors associated with these outcomes. Machine learning models predicted the site of DM, demonstrating an area under the curve of 0.74, 0.75, and 0.73 for brain, bone and visceral sites, respectively. Overall, most patients (57%) developed bone metastases, with increased odds associated with estrogen receptor (ER) positivity. Human epidermal growth factor receptor-2 (HER2) positivity and non-anthracycline chemotherapy regimens were associated with a decreased risk of bone DM, while brain metastasis was associated with ER-negativity. Furthermore, non-anthracycline chemotherapy alone was a significant predictor of visceral metastasis. Here, clinicopathologic and treatment variables used in ML prediction models predict the first site of metastasis in BC. Further validation may guide focused patient-specific surveillance practices.

Background: We characterized the risk factors and survival of metastatic breast cancer (MBC) patients with brain metastases (BrM) as the first and only site of disease in a large, retrospective cohort., Methods: MBC patients treated for BrM with radiation at a quaternary institution between 2005 and 2019 were identified. MBC patients with BrM but without concurrent extracranial metastases (ECM) or leptomeningeal disease (LMD) were classified as brain-only. Factors associated with brain-only MBC, brain-specific progression free survival (bsPFS) and overall survival (OS) were investigated., Results: A total of 691 patients with MBC and BrM were analyzed. Among them, 67 patients (9.7%, n = 67/691) presented with brain-only MBC without concurrent ECM/LMD. Within this subgroup, 40 patients (5.8%, n = 40/691) remained free of any ECM or LMD, while 17 patients (2.5%) developed LMD, and 10 patients (1.4%%) developed ECM with a median follow-up of 8 months (IQR 2-35). Patients with brain-only MBC were more likely to have a single BrM [OR 3.41 (1.62-7.19), p = 0.001] and either HER2+ [OR 3.3 (1.13-9.65), p = 0.03] or TNBC [OR 4.09 (1.42-11.74), p = 0.009] subtypes. Patients who presented with brain-only MBC also had significantly longer OS [HR 0.45, (0.22-0.86), p = 0.008] and a trend toward longer bsPFS [HR 0.67 (0.44-1.03), p = 0.05] compared to those with concurrent ECM/LMD., Conclusion: Patients with brain-only MBC had a longer bsPFS and OS than those with ECM. Patients with HER2+ and TNBC were more likely to have brain-only disease compared to those with HR+/HER2- MBC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: We examined the impact of non-adherence to adjuvant endocrine therapy (ET) on the risk and site of recurrence among older women with early stage, hormone receptor positive (HR+) breast cancer (EBC)., Methods: A population-based cohort of women age ≥ 65 years with T1N0 HR + EBC who were diagnosed between 2010 and 2016 and treated with breast-conserving surgery (BCS) + ET was identified. Treatment and outcomes were ascertained through linkage with administrative databases. ET non-adherence was examined as a time-dependent covariate in multivariable cause-specific Cox regression models to evaluate its effect on the risks of ipsilateral local recurrence (LR), contralateral breast cancer, and distant metastases., Results: The population cohort includes 2637 women; 73% (N = 1934) received radiation (RT) + ET and 27% (N = 703) received ET alone. At a median follow-up of 8.14 years, the first event was LR in 3.6% of women treated with ET alone and 1.4% for those treated with RT + ET (p < 0.001); the risk of distant metastases was < 1% in both groups. The proportion of time adherent to ET was 69.0% among those treated with RT + ET and 62.8% for those treated with ET alone. On multivariable analysis, increasing proportion of time non-adherent to ET was associated with increased risk of LR ((HR = 1.52 per 20% increase in time; 95%CI 1.25, 1.85; p < 0.001), contralateral BC (HR = 1.55; 95%CI 1.30, 1.84; p < 0.001), and distant metastases (HR = 1.44; 95%CI 1.08, 1.94; p = 0.01) but absolute risks were low., Conclusion: Non-adherence to adjuvant ET was associated with an increased risk of recurrence, but absolute recurrence rates were low., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Stereotactic body radiotherapy (SBRT) has emerged as a technique to treat oligoprogressive sites among patients with breast cancer who are otherwise doing well on systemic therapy. This study systematically reviewed the efficacy and safety of SBRT in the setting of oligoprogressive breast cancer. A literature search was conducted in the MEDLINE database. Studies regarding SBRT and oligoprogressive breast cancer were included. Key outcomes of interest were toxicity, local control, progression, and overall survival. From 863 references, five retrospective single-center cohort studies were identified. All studies included patients with both oligometastatic and oligoprogressive disease; 112 patients with oligoprogressive breast cancer were identified across these studies. Patient age ranged from 22 to 84, with a median of 55 years of age. Most patients had hormone-receptor-positive and HER2-negative disease. SBRT doses varied from 24 to 60 Gy in 1-10 fractions based on the location/size of the lesion. Forty toxicity events were reported, of which the majority ( n = 25, 62.5%) were grade 1-2 events. Among 15 patients who received SBRT concurrently with a CDK4/6 inhibitor, 37.5% of patients experienced grade 3-5 toxicities. Progression-free and overall survival ranged from 17 to 57% and 62 to 91%, respectively. There are limited data on the role of SBRT in oligoprogressive breast cancer, and prospective evaluation of this strategy is awaited to inform its safety and efficacy.

The approval of CDK4/6 inhibitors has dramatically improved care for the treatment of HR+/HER2- advanced breast cancer, but navigating the rapidly-expanding treatment evidence base is challenging. In this narrative review, we provide best-practice recommendations for the first-line treatment of HR+/HER2- advanced breast cancer in Canada based on relevant literature, clinical guidelines, and our own clinical experience. Due to statistically significant improvements in overall survival and progression-free survival, ribociclib + aromatase inhibitor is our preferred first-line treatment for de novo advanced disease or relapse ≥12 months after completion of adjuvant endocrine therapy and ribociclib or abemaciclib + fulvestrant is our preferred first-line treatment for patients experiencing early relapse. Abemaciclib or palbociclib may be used when alternatives to ribociclib are needed, and endocrine therapy can be used alone in the case of contraindication to CDK4/6 inhibitors or limited life expectancy. Considerations for special populations-including frail and fit elderly patients, as well as those with visceral disease, brain metastases, and oligometastatic disease-are also explored. For monitoring, we recommend an approach across CDK4/6 inhibitors. For mutational testing, we recommend routinely performing ER/PR/HER2 testing to confirm the subtype of advanced disease at the time of progression and to consider ESR1 and PIK3CA testing for select patients. Where possible, engage a multidisciplinary care team to apply evidence in a patient-centric manner.

We aimed to evaluate the expression of the "targetable" androgen receptor (AR) in breast cancer brain metastases (BrM). An established, retrospective 57-patient cohort with metastatic breast cancer who underwent surgery for BrM at the Sunnybrook Odette Cancer Centre between 1999-2013 was studied. AR expression in BrM samples was assessed in triplicate using immunohistochemistry (IHC). AR positive status was defined as nuclear AR expression ≥ 10% by IHC using the SP107 antibody. The median age of patients was 52 years (range 32-85 years). 28 (49%) of BrM were HER2+, 17 (30%) were hormone receptor positive (HR+)/HER2-, and 12 (21%) were triple negative breast cancers (TNBCs). 56% (n = 32/57) of BrM were AR positive, and median AR expression was 20% (CI 1.6-38.3%). AR expression was different across breast cancer subtypes; AR was most frequently expressed in HER2+ (n = 21/28), followed by HR+/HER2- (n = 9/17), and lowest in TNBC (n = 2/12) BrM ( p = 0.003). Patients with AR positive versus AR negative BrM had similar overall survival (12.5 vs. 7.9 months, p = 0.6), brain-specific progression-free survival (8.0 vs. 5.1 months, p = 0.95), and time from breast cancer diagnosis to BrM diagnosis (51 vs. 29 months, p = 0.16). AR is expressed in the majority of breast cancer BrM and represents a potential therapeutic target.

Importance: Intracranial metastatic disease (IMD) is a severe complication of cancer with profound prognostic implications. Patients with IMD in the setting of limited or stable extracranial disease (IMD-SE) may represent a unique and understudied subset of patients with IMD with superior prognosis., Objective: To evaluate overall survival (OS), progression-free survival (PFS), and intracranial PFS (iPFS) in patients with IMD-SE secondary to any primary cancer., Data Sources: Records were identified from MEDLINE, EMBASE, CENTRAL, and gray literature sources from inception to June 21, 2021., Study Selection: Studies in English reporting OS, PFS, or iPFS in patients with IMD-SE (defined as IMD and ≤2 extracranial metastatic sites) and no prior second-line chemotherapy or brain-directed therapy were selected., Data Extraction and Synthesis: Author, year of publication, type of study, type of primary cancer, and outcome measures were extracted. Random-effects meta-analyses were performed to estimate effect sizes, and subgroup meta-analysis and metaregression were conducted to measure between-study differences in February 2022., Main Outcomes and Measures: The primary end point was OS described as hazard ratios (HRs) and medians for comparative and single-group studies, respectively. Secondary end points were PFS and iPFS., Results: Overall, 68 studies (5325 patients) were included. IMD-SE was associated with longer OS (HR, 0.52; 95% CI, 0.39-0.70) and iPFS (HR, 0.63; 95% CI, 0.52-0.76) compared with IMD in the setting of progressive extracranial disease. The weighted median OS estimate for patients with IMD-SE was 17.9 months (95% CI, 16.4-22.0 months), and for patients with IMD-PE it was 8.0 months (95% CI, 7.2-12.8 months). Pooled median OS for all patients with IMD-SE was 20.9 months (95% CI, 16.35-25.98 months); for the subgroup with breast cancer it was 20.2 months (95% CI, 10.43-38.20 months), and for non-small cell lung cancer it was 27.5 months (95% CI, 18.27-49.66 months). Between-study heterogeneity for OS and iPFS were moderate (I2 = 56.5%) and low (I2 = 0%), respectively., Conclusions and Relevance: In this systematic review and meta-analysis of patients with IMD-SE, limited systemic disease was associated with improved OS and iPFS. Future prospective trials should aim to collect granular information on the extent of extracranial disease to identify drivers of mortality and optimal treatment strategies in patients with brain metastases.

Background: Curative intent cancer treatment needs to be balanced with patient comorbidities and quality of life when treating older women with breast cancer. We examined consultation patterns and association of age at diagnosis with lack of specialist cancer consultations for older women with breast cancer., Methods: We conducted a population-based retrospective cohort study of older women (≥ 70 years of age) with incident, non-metastatic breast cancer (2010-2018) by linking administrative databases in Ontario, Canada. The outcomes of interest were lack of specialist cancer consultation (surgeon, medical oncology, or radiation oncology) within 12 months of diagnosis. Association of age with lack of specialist cancer consultation was examined using Poisson regression modeling., Results: Of 21,849 older women, 2.4% (n = 517) did not have any specialist cancer consultation within 12 months of diagnosis; lack of any specialist cancer consultation increased with age (0.8% for age 70-74 years, 1.3% for age 75-79 years, 2.5% for age 80-84 years, and 7.0% for age ≥ 85 years; p < 0.001). The proportion of patients who did not have consultations with surgeons, medical oncologists, and radiation oncologists was 8.6% (n = 1888), 34.4% (n = 7510), and 24.7% (n = 5404), respectively. Older age group was independently associated with an increased likelihood of lacking any specialist consultation, as well as not receiving surgical and medical oncology consultations., Conclusion: More than one-third of women ≥ 70 years of age with non-metastatic breast cancer did not have a consultation with a medical oncologist, with women aged ≥ 85 years least likely to have a medical oncology consultation., (© 2022. Society of Surgical Oncology.)

Background: To evaluate the potential intracranial efficacy of immunotherapy among patients with breast cancer brain metastases (BrM), we analyzed the immunohistochemical expression of programmed death-ligand 1 (PD-L1), a predictive biomarker of response to immunotherapy., Methods: In this single-center retrospective cohort study, consecutive patients with breast cancer BrM (immunotherapy naïve) who underwent surgery for BrM at Sunnybrook Health Sciences Center between July 1999 and June 2013 were identified. PD-L1 expression by immunohistochemistry (IHC) was assessed on BrM samples in triplicate; PD-L1 positive status was defined as PD-L1 expression ≥1% on tumor-infiltrating cells as a percentage of tumor area using the Ventana SP142 antibody. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) status was determined using 2018 ASCO/CAP guidelines., Results: The median patient age at the time of BrM diagnosis was 52 (range 32-85). PD-L1 expression using the SP42 antibody was identified in 9 out of 59 (15.3%) breast cancer BrM. The frequency of PD-L1 positive BrM by subtype is as follows: TNBC ( n = 3/12, 25.0%), HER2+/HR- ( n = 3/14, 21.4%), HR+/HER2- ( n = 2/18, 11.1%), and HER2+/HR+ ( n = 1/14, 7.1%). 24-month brain-specific progression-free survival was 66.7% (95% CI 37.9%-100%) among patients with PD-L1 positive BrM versus 42% (95% CI 26.6%-67.3%) among those with PD-L1 negative BrM (log-rank P -value .142)., Conclusions: One in 7 patients in our cohort had PD-L1 positive BrM; this proportion was highest (25%) among those with TNBC. Intracranial efficacy of immunotherapy warrants further study, particularly among patients with treatment-naïve metastatic TNBC, for whom extracranial efficacy has already been established., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: The 49% decrease in breast cancer mortality since 1986 has increased the number of breast cancer survivors requiring survivorship care. The purpose of this analysis was to estimate the 2022 prevalence of breast cancer survivors diagnosed within the past 15 years among Canadian women., Methods: We extracted the projected female breast cancer cases from 2007 to 2021 and rates of net survival (competing noncancer causes of death removed) from the Canadian Cancer Society's statistical reports. Overall survival was extracted from published Ontario data. Using known survival rates for 1, 5, 10, and 15 years, we interpolated remaining years and applied the corresponding net and overall survival rates to the projected cases for each year from 2007 to 2021 to determine survivors in 2022. Prevalence for predefined age groups was also calculated. As an example of excess healthcare costs attributable to breast cancer, we calculated the excess costs of heart failure hospitalizations., Results: From 2007 to 2021, there were 370,756 breast cancer cases. Using net survival, 318,429 (85.9%) of these patients were projected to survive breast cancer by 2022, a prevalence of 2.1% of Canadian women. Using overall survival, prevalence was 1.8%. Prevalence increased with age group, from 0.01% of those aged 20 to 24 years to 12.7% of those aged ≥90 years, and from 1.0% among the working and/or child-raising (age 20-64 years) to 5.4% among elderly populations (age ≥65 years). Among these survivors, 24.9% of projected heart failure hospitalizations would be in excess of those among matched control subjects, with projected excess costs of $16.5 million CAD. Given the excess healthcare costs, potential for reduced contributions to the workforce, and reduced quality of life associated with long-term impairments and risk of excess non-breast cancer death, enhanced breast cancer survivorship care is warranted., Conclusions: With an overall prevalence of 2% among Canadian women, breast cancer survivors represent an increasing segment of the working-age and elderly populations.

Purpose: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post-cyclin-dependent kinase (CDK) 4/6 inhibitor progression., Patients and Methods: Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status., Results: At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44-23.87); fulvestrant: 13.7% (7/51; 5.70-26.26); risk difference -1.96% (95% CI, -16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94-3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84-3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61-1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status., Conclusions: Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting., (©2022 The Authors; Published by the American Association for Cancer Research.)

Importance: Approximately 1 in 7 patients with metastatic breast cancer (MBC) will receive radiotherapy for brain metastases (BRM). Significant differences in cumulative incidence of BRM by breast cancer subtype may inform future BRM screening protocols., Objective: To describe cumulative incidence of BRM among patients with de novo MBC., Design, Setting, and Participants: In this population-based cohort study, population health administrative databases in Ontario, Canada, held at the ICES were used to identify patients diagnosed with de novo MBC between 2009 and 2018. Given that a code for BRM does not exist within ICES, we analyzed the incidence of radiotherapy for BRM. The median (IQR) follow-up was 19.3 (6.2-39.5) months. A total of 100 747 patients with a new diagnosis of breast cancer between January 2009 and December 2018 were identified. Of these patients, 17 955 were excluded because they had previous or subsequent malignant neoplasms, 583 were excluded because they were younger than 18 years, 974 were excluded because there was an invalid Ontario Health Insurance Plan number or a date of death on or before the index date. Among 81 235 remaining patients, 3916 were identified as having de novo MBC., Exposures: Treatment with radiotherapy for breast cancer BRM., Main Outcomes and Measures: Cumulative incidence of radiotherapy for BRM accounting for the competing risk of death, and time from MBC diagnosis to brain radiotherapy. Kaplan-Meier analyses were performed for time-to-event end points. Logistic regression was used to account for confounding variables., Results: Among 3916 patients with MBC, 1215 (31.0%) had HR-positive/ERBB2 (formerly HER2)-negative cancer, 310 (7.9%) had ERBB2-positive/HR-positive cancer, 200 (5.1%) had ERBB2-positive/HR-negative cancer, 258 (6.6%) had TNBC, and the remaining 1933 patients (49.4%) had an unknown breast cancer subtype. The median (IQR) age at diagnosis was 63 (52-75). A total of 549 (14.0%) underwent stereotactic radiosurgery or whole brain radiotherapy for breast cancer BRM. Cumulative incidence of BRM was higher among patients with ERBB2-positive/HR-negative breast cancer (34.7%), ERBB2-positive/HR-positive breast cancer (28.1%), and triple-negative breast cancer (21.9%) compared to those with HR-positive/ERBB2-negative breast cancer (12.1%). The median (IQR) time from MBC diagnosis to brain radiotherapy ranged from 7.5 (2.3-17.4) months for patients with TNBC to 19.8 (12.2-35.1) months for those with ERBB2-positive/HR-positive breast cancer., Conclusions and Relevance: Incidence and time to development of BRM vary significantly by breast cancer subtype. A better understanding of the biology of intracranial metastatic disease may help inform potential screening programs or preventative interventions.

Introduction: In this study, we investigate factors associated with radionecrosis (RN) in HER2 + (human epidermal growth factor receptor 2) patients with brain metastases (BrM) treated with stereotactic radiosurgery (SRS)., Methods: Patients with HER2 + breast cancer BrM treated with SRS (2010-2020) were identified from an institutional database. The incidence of RN was determined per treated BrM according to serial imaging and/or histology. Factors associated with RN such as age, RT dose, BrM volume, and initiation of Trastuzumab Emtansine (T-DM1) were investigated with univariate and multivariable analyses (MVA)., Results: 67 HER2 + patients with 223 BrM were identified. 21 patients (31.3%) were treated with T-DM1 post-SRS, including 14 patients (20.9%) who received T-DM1 within 12 months of SRS. The median follow-up was 15.6 (interquartile range (IQR) 5.4-35.3) months. The overall probability of RN post-SRS was 21.6% (95% confidence interval (CI) 2.7-10.7), and the 1 and 2 year risk was 6.7% (95% CI 2.7-10.7) and 15.2% (95% CI 9.2-21.3). MVA identified T-DM1 treatment post-SRS (hazard ratio (HR) 2.5, 95% CI 1.2-5.3, p = 0.02) and equivalent dose in 2 Gy fractions (EQD2) > 90 Gy 2 (HR 2.4, 95% CI 1.1-5.1, p = 0.02) as predictors of RN. Patients treated with T-DM1 and SRS had a 29.9% (95% CI 15.3-44.6%) probability of RN, with a 25.2% (95% CI 12.8-37.6%) risk at 1- and 2 years post-T-DM1. The majority of RN were symptomatic (71%), with a median time to RN of 4.8 months., Conclusion: T-DM1 exposure post-SRS was associated with a higher risk of RN among patients with HER2 + BrM., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To examine the association between Karnofsky Performance Status ("KPS") and brain-specific progression-free survival ("bsPFS") among patients with breast cancer brain metastases ("BCBrM")., Methods: Using a previously compiled retrospective cohort of 683 patients who were treated for BCBrM with surgery and/or radiotherapy at the Sunnybrook Odette Cancer Centre from 2008-2018, electronic records were reviewed to impute KPS scores at the time of BCBrM diagnosis. Patients were then grouped into KPS ≤60 and KPS >60 cohorts. The dataset was analyzed to identify variables that were prognostic for bsPFS and/or overall survival ("OS") using univariable and multivariable Cox proportional hazards models., Results: The mean age of patients was 57 (range 24-93). Most patients ( n =622, 91%) had extracranial metastatic disease and 174 (25%) had leptomeningeal disease. 247 patients (36%) had hormone receptor ("HR")-positive/human endothelial growth factor receptor 2 ("HER2")-negative tumours, 189 (28%) had HER2-positive disease, and 153 (22%) had triple-negative breast cancer. Of the 331 patients (48%) who could be assigned a KPS cohort, 102 (31%) had KPS ≤60. Most patients were treated with whole brain radiotherapy ( n =498, 73%) and/or stereotactic radiosurgery ("SRS") ( n =128, 19%). Median bsPFS was 9 months (95% CI 8-10 months) and median OS was not reached. In univariable analyses, KPS ≤60, presence of leptomeningeal disease, neurological symptoms, ≥2 brain metastases, and not undergoing SRS were factors associated with shorter bsPFS. In a multivariable analysis, KPS ≤60 was the only statistically significant determinant of bsPFS (HR 1.86, 95% CI 1.20-2.88). Although survival data was limited, KPS ≤60 was associated with shorter OS in both univariable (HR 3.12, 95% CI 1.85-5.26) and multivariable (HR 2.95, 95% CI 1.55-5.58) analyses., Conclusion: Patients with BCBrM who have a KPS ≤60 have significantly shorter bsPFS and OS than those with KPS >60. KPS should be documented routinely at the time of diagnosis of brain metastases to improve prognostication., Competing Interests: Author KJJ reports the following: Speaker/advisor board/consultant for: Amgen, Apo Biologix, AstraZeneca, Eli Lilly, Esai, Exact Sciences, Knight Therapeutics, Pfizer, Seagen, Merck, Novartis, Roche. Research funding: Eli Lilly, Astra Zeneca, Seagen. Author ME reports personal fees from Mount Sinai Hospital, London Health Sciences Centre and Sunnybrook Health Sciences Centre for statistical consulting. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Freeman, Ennis and Jerzak.)

Intracranial metastatic disease (IMD) is a prevalent complication of cancer that significantly limits patient survival and quality of life. Over the past half-century, our understanding of the epidemiology and pathogenesis of IMD has improved and enabled the development of surveillance and treatment algorithms based on prognostic factors and tumor biomolecular characteristics. In addition to advances in surgical resection and radiation therapy, the treatment of IMD has evolved to include monoclonal antibodies and small molecule antagonists of tumor-promoting proteins or endogenous immune checkpoint inhibitors. Moreover, improvements in the sensitivity and specificity of imaging as well as the development of new serological assays to detect brain metastases promise to revolutionize IMD diagnosis. In this review, we will explore current treatment principles in patients with IMD, including the emerging role of targeted and immunotherapy in select primary cancers, and discuss potential areas for further investigation., Competing Interests: SD acts as a consultant for Medexus and is on the advisory board for the Subcortical Surgery Group and Xpan Medical as well as the Speaker’s Board for the Congress of Neurological Surgeons, American Association of Neurological Surgeons, and Society for NeuroOncology. KJ is a speaker/advisor board/consultant for: Amgen, Astra Zeneca, Apo Biologix, Eli Lilly, Esai, Exact Sciences, Knight Therapeutics, Pfizer, Merck, Novartis, Purdue Pharma, Roche, Seagen, Viatris; and receives research funding from Eli Lilly, Astra Zeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Gaebe, Jerzak, Cheema, Sahgal and Das.)

Background: Breast cancer is the most common cancer among women worldwide and the second leading cause of brain metastases (BrM). We assessed the treatment patterns and outcomes of women treated for breast cancer BrM at our institution in the modern era of stereotactic radiosurgery (SRS)., Materials and Methods: We conducted a retrospective analysis of women (≥18 years of age) with metastatic breast cancer who were treated with surgery, whole brain radiotherapy (WBRT), or SRS to the brain at the Sunnybrook Odette Cancer Centre, Toronto, Canada, between 2008 and 2018. Patients with a history of other malignancies and those with an uncertain date of diagnosis of BrM were excluded. Descriptive statistics were generated and survival analyses were performed with subgroup analyses by breast cancer subtype., Results: Among 683 eligible patients, 153 (22.4%) had triple-negative breast cancer, 188 (27.5%) had HER2+, 246 (36.0%) had hormone receptor (HR)+/HER2-, and 61 (13.3%) had breast cancer of an unknown subtype. The majority of patients received first-line WBRT (n = 459, 67.2%) or SRS (n = 126, 18.4%). The median brain-specific progression-free survival and median overall survival (OS) were 4.1 months (interquartile range [IQR] 1.0-9.6 months) and 5.1 months (IQR 2.0-11.7 months) in the overall patent population, respectively. Age >60 years, presence of neurological symptoms at BrM diagnosis, first-line WBRT, and HER2- subtype were independently prognostic for shorter OS., Conclusion: Despite the use of SRS, outcomes among patients with breast cancer BrM remain poor. Strategies for early detection of BrM and central nervous system-active systemic therapies warrant further investigation., Implications for Practice: Although triple-negative breast cancer and HER2+ breast cancer have a predilection for metastasis to the central nervous system (CNS), patients with hormone receptor-positive/HER2- breast cancer represent a high proportion of patients with breast cancer brain metastases (BrM). Hence, clinical trials should include patients with BrM and evaluate CNS-specific activity of novel systemic therapies when feasible, irrespective of breast cancer subtype. In addition, given that symptomatic BrM are associated with shorter survival, this study suggests that screening programs for the early detection and treatment of breast cancer BrM warrant further investigation in an era of minimally toxic stereotactic radiosurgery., (© 2021 AlphaMed Press.)

Competing Interests: Declaration of interests KJJ reports speaker, advisory board, or consultant roles for Amgen, AstraZeneca, Apo Biologix, Eli Lilly, Esai, Genomic Health, Knight Therapeutics, Merck, Myriad Genetics Inc, Pfizer, Roche, Novartis, and Purdue Pharma, and research funding from Eli Lilly and AstraZeneca. The other authors declare no competing interests.

Background: Evaluating histologic grade for breast cancer diagnosis is standard and associated with prognostic outcomes. Current challenges include the time required for manual microscopic evaluation and interobserver variability. This study proposes a computer-aided diagnostic (CAD) pipeline for grading tumors using artificial intelligence., Methods: There were 138 patients included in this retrospective study. Breast core biopsy slides were prepared using standard laboratory techniques, digitized, and pre-processed for analysis. Deep convolutional neural networks (CNNs) were developed to identify the regions of interest containing malignant cells and to segment tumor nuclei. Imaging-based features associated with spatial parameters were extracted from the segmented regions of interest (ROIs). Clinical datasets and pathologic biomarkers (estrogen receptor, progesterone receptor, and human epidermal growth factor 2) were collected from all study subjects. Pathologic, clinical, and imaging-based features were input into machine learning (ML) models to classify histologic grade, and model performances were tested against ground-truth labels at the patient-level. Classification performances were evaluated using receiver-operating characteristic (ROC) analysis., Results: Multiparametric feature sets, containing both clinical and imaging-based features, demonstrated high classification performance. Using imaging-derived markers alone, the classification performance demonstrated an area under the curve (AUC) of 0.745, while modeling these features with other pathologic biomarkers yielded an AUC of 0.836., Conclusion: These results demonstrate an association between tumor nuclear spatial features and tumor grade. If further validated, these systems may be implemented into pathology CADs and can assist pathologists to expeditiously grade tumors at the time of diagnosis and to help guide clinical decisions.

Purpose: To compare clinical-pathologic characteristics and outcomes of pregnancy-associated, post-partum (PP) and nulliparous (NP) breast cancer (BC) patients and explore mediators of the poor prognosis associated with post-partum BC., Methods: A prospective database of 233 women ≤ 40 years of age diagnosed with BC between February 2008 and January 2015 was analysed. Clinical-pathologic characteristics and outcomes among pregnant, PP and NP patients were compared using chi-square or Kruskal-Wallis tests. The Kaplan-Meier method was used to estimate disease-free survival (DFS), distant DFS and overall survival (OS). Survival curves were compared using the log-rank test. Univariable Cox proportional hazards regression models were used to evaluate factors that were potentially prognostic for the clinical outcomes of interest; a multivariable Cox model was constructed using a forward stepwise selection process. Androgen receptor (AR), GATA3, PDL1 status and the presence/absence of tumour-infiltrating lymphocytes (TILs) were assessed when possible. Pre-treatment neutrophil and lymphocyte counts were abstracted retrospectively. Statistical significance was defined as a p value ≤ 0.05., Results: Women ≤ 2 years PP had a numerically higher incidence of lymph node-positive and high-grade disease and were significantly more likely to have estrogen receptor-negative BC compared to NP controls. With a median follow-up of 7.2 years, increasingly poor outcomes were observed among NP (longest OS), > 2 years PP, ≤ 2 years PP and pregnant (shortest OS) patients, but these differences were not statistically significant. The ≤ 2 years PP group had significantly lower AR expression, a strong trend toward higher PDL1 expression and a higher expression of stromal TILs compared to NP women., Conclusions: PPBC patients had numerically lower DFS and OS compared to NP controls. Higher PDL1 and stromal TILs in PPBC suggest that adjuvant immunotherapy may be effective in the post-partum BC subgroup., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Postpartum breast cancer (PPBC) - which according to new data, can extend to 5-10 years after the birth - are estimated to represent 35-55% of all cases of breast cancer in women younger than 45 years. Increasing clinical evidence indicates that PPBC represents a high-risk form of breast cancer in young women with an approximately 2-fold increased risk for metastasis and death. Yet, the exact mechanisms that underlay this poor prognosis are incompletely understood and, hence, it is unknown why postpartum breast cancer has an enhanced risk for metastasis or how it should be effectively targeted for improved survival. This article is an accompanying resource of the original article entitled "Breast cancer diagnosed in the post-weaning period is indicative for a poor outcome" and present epidemiological data that compare standard prognostic parameters, first site of metastatic disease and survival and metastatic rates in young women with primary invasive breast cancer diagnosed within two years postpartum (PP-BC), in young women diagnosed during pregnancy (Pr-BC) and nulliparous women (NP-BC). Via an international collaboration of 13 centres participating in the International Network on Cancer, Infertility and Pregnancy (INCIP), retrospective data of 1180 patients with primary invasive breast cancer, aged 25-40 years and diagnosed between January 1995 and December 2017 were collected. In particular, tumour-, patient, and therapy-related characteristics were collected. Furthermore, patient files were reviewed thoroughly to assess, for each parity, if and for how long breastfeeding was given. For PP-BC patients, breastfeeding history was used to differentiate breast cancers identified during lactation (PP-BC DL ) from those diagnosed post-weaning (PP-BC PW ). Primary exposures were prior childbirth or no childbirth, time between most recent childbirth and breast cancer diagnosis, time between cessation of lactation and breast cancer diagnosis and time between breast cancer diagnosis and metastasis or death. Distribution of standard prognostic parameters and first site of distant metastasis among study groups was determined applying fisher's exact, chi-squared, One-Way ANOVA or Kruskal-Wallis tests or logistic regression models, where applicable. The risks for metastasis and death were assessed using Cox proportional hazards models. A subgroup analysis was performed in PP-BC PW patients that never lactated (PP-BC PW/NL ), lactated ≤3 months (PP-BC PW/Lshort ) or lactated >3 months (PP-BC PW/Llong )., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article., (© 2021 The Author(s). Published by Elsevier Inc.)

Background: In young women, a breast cancer diagnosis after childbirth increases the risk for metastasis and death. Studies in rodents suggest that post-weaning mammary gland involution contributes to the poor prognosis of postpartum breast cancers. However, this association has not been investigated in humans, mainly because of missing information on the patient's lactation status at diagnosis., Patients and Methods: Clinicopathological data of 1180 young women with primary invasive breast cancer, diagnosed within 2 years postpartum (PP-BC), during pregnancy (Pr-BC), or nulliparous (NP-BC), were collected. For PP-BC patients, breastfeeding history was retrieved to differentiate breast cancers identified during lactation (PP-BC DL ) from those diagnosed post-weaning (PP-BC PW ). Differences in prognostic parameters, first site of distant metastasis, and risks for metastasis and death were determined between patient groups., Results: Cox proportional hazard models pointed to a twofold increased the risk of metastasis and death in PP-BC PW patients compared with PP-BC DL (hazard ratio [HR] 2.1 [P DRS  = 0.021] and 2.9 [P OS  = 0.004]), Pr-BC (HR 2.1 [P DRS <0.001] and 2.3 [P OS <0.001]) and NP-BC (HR 2.1 [P DRS <0.001] and 2.0 [P OS <0.001]) patients. Prognosis was poorest for PP-BC PW patients who did not breastfeed or only for ≤ 3 months before diagnosis. This could not fully be attributed to differences in standard prognostic characteristics. In addition, PP-BC PW tumours showed a 3- to 8-fold increased risk to metastasise to the liver, yet this did not correlate with the poor outcome of this patient cohort., Conclusions: Breast cancer diagnosed shortly after weaning specifically adds to the poor prognosis in women diagnosed with PP-BC. Apart from the importance of an increased awareness, these data show that detailed lactation data need to be registered when breast cancer outcome in young women is investigated., Competing Interests: Conflict of interest statement 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 © 2021 Elsevier Ltd. All rights reserved.)

Importance: Targeted therapies have been hypothesized to prolong survival in the treatment of patients with intracranial metastatic disease (IMD) but, paradoxically, increase IMD incidence by improving systemic disease control and prolonging survival from the primary tumor. The real-world benefits of targeted therapy in treating patients with IMD are unclear, as clinical trials have excluded patients with IMD and lacked end points that report intracranial outcomes., Objective: To assess the association of targeted therapy and IMD with patient survival., Design, Setting, and Participants: This retrospective cohort study included all patients in Ontario, Canada, who received a diagnosis of IMD from April 2005 to January 2018 with primary diagnoses of breast cancer, lung or bronchus cancer, or melanoma and control patients who were matched by primary disease without IMD. The data were analyzed between March and October 2020., Exposures: EGFR-, ERBB2 (HER2-), or BRAF-targeted therapy or IMD status., Main Outcomes and Measures: Kaplan-Meier and multivariable Cox regression analyses were performed to compare overall survival (OS) between patient subcohorts divided by primary disease and stratified by targeted therapy receipt or IMD status., Results: In this cohort of 26 676 patients with IMD and breast cancer, lung and bronchus cancer, or melanoma, 57% of patients were women, and the median age at IMD diagnosis was 64 years (interquartile range, 56-72 years). Post-IMD targeted therapy was associated with prolonged OS in patients with ERBB2-positive breast cancer (hazard ratio [HR], 0.41; 95% CI, 0.33-0.50), EGFR-positive lung cancer (HR, 0.28; 95% CI, 0.23-0.34), and BRAF-positive melanoma (HR, 0.20; 95% CI, 0.14-0.29) compared with those who did not receive post-IMD targeted therapy. The presence of IMD was associated with shorter OS in patients with metastatic ERBB2-positive breast cancer (HR, 1.80; 95% CI, 1.56-2.08) and metastatic EGFR-positive lung cancer (HR, 1.22; 95% CI, 1.08-1.39) but not metastatic BRAF-positive melanoma (HR, 1.11; 95% CI, 0.77-1.61) compared with those without IMD., Conclusions and Relevance: The findings of this cohort study suggest an association between real-world use of targeted therapies and prolonged OS in patients with IMD in the setting of ERBB2-positive breast cancer, EGFR-positive lung cancer, and BRAF-positive melanoma. Including patients with IMD in clinical trials and using end points that interrogate IMD will be critical to determine the role of targeted therapies in treating patients with IMD.

Background: Tumor multigene next-generation sequencing (NGS) is increasingly being offered to cancer patients to guide clinical management and determine eligibility for clinical trials. We undertook a review of studies examining the knowledge and attitudes of patients and oncologists regarding the primary results and potential secondary findings of such testing., Materials and Methods: A search was conducted through the MEDLINE database using the following keywords: "neoplasms" and "molecular sequencing / genome sequencing / tumor profiling / NGS / whole exome sequencing" and "patient / oncologist" and "knowledge / attitudes / satisfaction / experience / evaluation / perspective / practice / preference." Articles meeting the inclusion criteria and additional relevant articles from their references were selected., Results: From 1,142 publications identified by the search and 9 from references, 21 publications were included in the final review. Patients generally had positive attitudes toward tumor NGS despite relatively little knowledge of test-related genetics concepts, but their expectations often exceeded the reality of low clinical utility. Patients with higher education and greater genetics knowledge had more realistic expectations and a more altruistic view of the role of NGS. Attitudes toward disclosure of secondary findings were highly variable. Oncologists had poor to moderate genomic literacy; they communicated challenges with tempering patient expectations and deciding what information to disclose., Conclusion: Patients considering undergoing tumor NGS should be provided with easily understandable resources explaining the procedure, goals, and probable outcomes, whenever possible based on evidence-based guidelines. Continuing medical education programs on this topic for oncology health care professionals should strive to improve their genomic literacy and instruct them on how to optimally present this information to their patients., Implications for Practice: Oncologists are increasingly offering tumor multigene testing to patients with advanced cancers to guide more "personalized" treatment and/or determine eligibility for clinical trials. However, patients often have inadequate understanding and unrealistic expectations. Oncologists must ensure that they themselves have sufficient knowledge of the benefits and limitations of testing and must provide their patients with appropriate educational resources. Prior to testing, patients should be told the likelihood of finding a mutation in their specific tumor type for which a targeted treatment or clinical trial is available. Patients also need clear information about the possibility and implications of secondary findings., (© 2021 AlphaMed Press.)