Pan-Canadian Analysis of Practice Patterns in Small Cell Carcinoma of the Cervix: Insights from a Multidisciplinary Survey.

Small-cell neuroendocrine carcinoma of the cervix (SCNECC) is a rare cancer with poor prognosis, with limited data to guide its treatment. The objective of this study was to evaluate practice patterns in the management of SCNECC. A 23-question online survey on management of SCNECC was disseminated to Canadian gynecologic oncologists (GO), radiation oncologists (RO) and medical oncologists (MO). In total, 34 practitioners from eight provinces responded, including 17 GO, 13 RO and four MO. During staging and diagnosis, 74% of respondents used a trimodality imaging approach, and 85% tested for neuroendocrine markers. In early-stage (1A1-1B2) SCNECC, 87% of practitioners used a surgical-based approach with various adjuvant and neoadjuvant treatments. In locally advanced (1B3-IVA) SCNECC, 53% favored primary chemoradiation, with cisplatin and etoposide, with the remainder using surgical or radiation-based approaches. In metastatic and recurrent SCNECC, the most common first-line regimen was etoposide and platinum, and 63% of practitioners considered clinical trials in the first line setting or beyond. This survey highlights diverse practice patterns in the treatment of SCNECC. Interdisciplinary input is crucial to individualizing multimodality treatment, and there is a need for prospective trials and intergroup collaboration to define the optimal approach towards managing this rare cancer type.

Human Epidermal Growth Factor Receptor 2-Low Breast Cancer Brain Metastases: An Opportunity for Targeted Systemic Therapies in a High-Need Patient Population.

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.

Brain Metastases in the Setting of Stable Versus Progressing Extracranial Disease Among Patients With Metastatic Breast Cancer.

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.

Appraisal of Systemic Treatment Strategies in Early HER2-Positive Breast Cancer-A Literature Review.

BACKGROUND: The overexpression of the human epidermal growth factor receptor 2 (HER2+) accounts for 15-20% of all breast cancer phenotypes. Even after the completion of the standard combination of chemotherapy and trastuzumab, relapse events occur in approximately 15% of cases. The neoadjuvant approach has multiple benefits that include the potential to downgrade staging and convert previously unresectable tumors to operable tumors. In addition, achieving a pathologic complete response (pCR) following preoperative systemic treatment is prognostic of enhanced survival outcomes. Thus, optimal evaluation among the suitable strategies is crucial in deciding which patients should be selected for the neoadjuvant approach. METHODS: A literature search was conducted in the Embase, Medline, and Cochrane electronic libraries. CONCLUSION: The evaluation of tumor and LN staging and, hence, stratifying BC recurrence risk are decisive factors in guiding clinicians to optimize treatment decisions between the neoadjuvant versus adjuvant approaches. For each individual case, it is important to consider the most likely postsurgical outcome, since, if the patient does not obtain pCR following neoadjuvant treatment, they are eligible for adjuvant T-DM1 in the case of residual disease. This review of HER2-positive female BC outlines suitable neoadjuvant and adjuvant systemic treatment strategies for guiding clinical decision making around the selection of an appropriate therapy.

Androgen Receptor Is Expressed in the Majority of Breast Cancer Brain Metastases and Is Subtype-Dependent.

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.

PD-L1 expression in breast cancer brain metastases.

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.

Analysis of Rates of Brain Metastases and Association With Breast Cancer Subtypes in Ontario, Canada.

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.

Treatment Patterns and Outcomes of Women with Symptomatic and Asymptomatic Breast Cancer Brain Metastases: A Single-Center Retrospective Study.

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.

Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors - A systematic review and meta-analysis.

BACKGROUND: The use of immune checkpoint inhibitors (ICIs) has become standard therapy in many tumor sites. The aim of this study is to systematically review the literature to determine whether the incidence of immune-related adverse events (irAEs) after the use of ICIs is associated with clinical outcomes in all solid malignancies. METHODS: Embase and PubMed were searched from January 1st, 2000 until March 14, 2020 for relevant studies assessing the relationship between irAEs and treatment efficacy. Outcome measures of interest included: incidence of irAEs, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Of 3384 unique citations, 51 studies met inclusion criteria. Studies included melanoma (n = 21), lung (n = 19), renal (n = 4), urothelial (n = 1), head and neck (n = 2) and gastrointestinal cancers (n = 1). In patients with metastatic melanoma (n = 1474), the development of irAEs (irAE + versus irAE-) was associated with better weighted average OS (15.24 months (95% CI 9.95 to 20.5) versus 8.94 months (95% CI 7.76 to 10.1), HR = 0.46 (n = 640, CI 0.35-0.62, p < 0.00001), PFS (17.61 months (95% CI 10.1 to 25.1) versus 2.23 months (95% CI 1.77 to 2.68), HR = 0.51 (n = 1763, CI 0.42-0.63, p < 0.00001), and ORR (37.67% (95% CI 32.8 to 42.5) versus. 23.44% (95% CI 17.8 to 29.1). Similarly, in lung cancer patients, the ORR (irAE + versus. irAE-) was 41.49% (95% CI 36.5 to 46.5) versus 18.01% (95% CI 13.5 to 22.6). The weighted average PFS and OS were 8.97 months (95% CI 7.14 to 10.8) versus 3.06 months (95% CI 2.4 to 3.72) with HR = 0.46 (n = 1575, CI 0.39-0.54, p < 0.00001) and 19.07 months (95% CI 14.3 to 23.8) versus 7.45 months (95% CI 5.34 to 9.56) HR = 0.40 (n = 1085, CI 0.30-0.51, p < 0.00001), respectively. Improved treatment efficacy in patients who developed irAEs was also seen in renal cell carcinoma, urothelial and head and neck cancers. Notably, grade 3 or 4 irAEs were associated with increased ORR but worse OS. CONCLUSION: A positive association was noted between the development of irAEs and ORR, PFS, and OS in patients treated with ICIs, irrespective of disease site, type of ICI and irAE. Grade 3 or higher toxicities resulted in better ORR, but worse OS.

Esophageal carcinoma: Towards targeted therapies.

BACKGROUND: Patients with esophageal cancer are confronted with high mortality rates. Whether it is esophageal squamous cell carcinoma (ESCC) or esophageal adenocarcinoma (EAC), patients usually present at advanced stages, with treatment options traditionally involving chemotherapy in metastatic settings. With the comprehensive genomic characterization of esophageal cancers, targeted therapies are gaining interest and agents such as ramucirumab, trastuzumab and pembrolizumab are already being used for the treatment of EAC. CONCLUSIONS: Pembrolizumab has recently been FDA-approved for PD-L1 positive, locally advanced or metastatic ESCC. Despite comprehensive molecular characterization, however, available targed therapies for ESCC are still lagging behind. Herein, we discuss current trends towards more targeted therapies in esophageal cancers, taking into consideration unique features of ESCCs and EACs. Patients progressing on standard therapies should be subjected to genomic profiling and considered for clinical trials aimed at testing targeted therapies. Future targeted therapies may include CDK4/6 inhibitors, PARP inhibitors and inhibitors targeting the NRF2 and Wnt signaling pathways. Ultimately, optimized biomarker assays and next generation sequencing platforms may allow for the identification of subcategories of ESCC and EAC patients that will benefit from selective targeted therapies and/or combinations thereof.

CCAAT/enhancer binding protein delta (C/EBPδ) demonstrates a dichotomous role in tumour initiation and promotion of epithelial carcinoma.

BACKGROUND: CCAAT/enhancer binding protein delta (C/EBPδ,CEBPD), a gene part of the highly conserved basic-leucine zipper (b-ZIP) domain of transcriptional factors, is downregulated in 65% of high grade serous carcinomas of the ovary (HGSC). Overexpression of C/EBPδ in different tumours, such as glioblastoma and breast cancer either promotes tumour progression or inhibits growth and has low expression in normal tissue until activated by cytotoxic stressors. METHODS: Higher overall expression of C/EBPδ in the luteal phase of the menstrual cycle prompted us to investigate the role of C/EBPδ in carcinogenesis. In vitro experiments were conducted in fallopian tube cell samples and cancer cell lines to investigate the role of C/EBPδ in proliferation, migration, and the epithelial to mesenchymal transition. FINDINGS: Expression of C/EBPδ induced premature cellular arrest and decreased soft agar colony formation. Loss of C/EBPδ in epithelial cancer cell lines did not have significant effects on proliferation, yet overexpression demonstrated downregulation of growth, similar to normal fallopian tube cells. C/EBPδ promoted a partial mesenchymal to epithelial (MET) phenotype by upregulating E-cadherin and downregulating Vimentin and N-cadherin in FTE cells and increased migratory activity, which suggests a regulatory role in the epithelial-mesenchymal plasticity of these cells. INTERPRETATION: Our findings suggest that C/EBPδ regulates the phenotype of normal fallopian tube cells by acting on downstream regulatory factors that are implicated in the development of ovarian serous carcinogenesis. FUND: This study was funded by the CDMRP Ovarian Cancer program (W81WH-0701-0371, W81XWH-18-1-0072), the Princess Margaret Cancer Centre Foundation, Foundation for Women's Cancer - The Belinda-Sue/Mary-Jane Walker Fund, Colleen's Dream Foundation and Sylvester Comprehensive Cancer Center.

Reduced BRCA1 transcript levels in freshly isolated blood leukocytes from BRCA1 mutation carriers is mutation specific.

BACKGROUND: BRCA1 mutation carriers face a high lifetime risk of developing both breast and ovarian cancer. Haploinsufficiency is thought to predispose these women to cancer by reducing the pool of available BRCA1 transcript and protein, thereby compromising BRCA1 function. Whether or not cancer-free BRCA1 mutation carriers have lower messenger (m)RNA transcript levels in peripheral blood leukocytes has not been evaluated. The primary aim of this study was to characterize an association between BRCA1 mutation status and BRCA1 mRNA leukocyte expression levels among healthy women with a BRCA1 mutation. METHOD: RNA was extracted from freshly isolated peripheral blood leukocytes of 58 cancer-free, female participants (22 BRCA1 mutation carriers and 36 non-carriers). The expression levels of 236 cancer-associated genes, including BRCA1, were quantified using the Human Cancer Reference gene panel from the Nanostring Technologies nCounter Analysis System. RESULTS: Multivariate modeling demonstrated that carrying a BRCA1 mutation was the most significant predictor of BRCA1 mRNA levels. BRCA1 mRNA levels were significantly lower in BRCA1 mutation carriers compared to non-carriers (146.7 counts vs. 175.1 counts; P = 0.002). Samples with BRCA1 mutations within exon 11 had lower BRCA1 mRNA levels than samples with mutations within the 5' and 3' regions of the BRCA1 gene (122.1 counts vs. 138.9 and 168.6 counts, respectively; P = 0.003). Unsupervised hierarchical clustering of gene expression profiles from freshly isolated blood leukocytes revealed that BRCA1 mutation carriers cluster more closely with other BRCA1 mutation carriers than with BRCA1 wild-type samples. Moreover, a set of 17 genes (including BRCA1) previously shown to be involved in carcinogenesis, were differentially expressed between BRCA1 mutation carriers and non-carriers. CONCLUSION: Overall, these findings support the concept of BRCA1 haploinsufficiency wherein a specific mutation results in dosage-dependent alteration of BRCA1 at the transcriptional level. This study is the first to show a decrease in BRCA1 mRNA expression in freshly isolated blood leukocytes from healthy, unaffected BRCA1 mutation carriers.

Uninterrupted Sedentary Behavior Downregulates BRCA1 Gene Expression.

BRCA1 mutation carriers face a high lifetime risk of developing breast cancer. Physical activity induces broad transcriptional changes, and multiple studies have documented its beneficial effects across cancers. Because haploinsufficiency predisposes to breast cancer in these women, factors that increase BRCA1 levels may mitigate the effect of the mutation. Whether physical activity modulates BRCA1 expression and whether lifestyle factors could benefit women with a mutation remain unclear. The objective of this study was to systematically evaluate whether physical activity or sedentary behavior affects BRCA1 mRNA expression. Activity levels were assessed in 50 female participants (14 BRCA1 mutation carriers and 36 noncarriers) using the GT3X Actigraph accelerometer, and BRCA1 mRNA expression was quantified from peripheral blood lymphocytes using the Nanostring nCounter Analysis System. There was a significant negative correlation between the longest sedentary bout and BRCA1 mRNA expression (ρ = -0.32; P = 0.02). Women below the median for the longest sedentary bout had significantly higher BRCA1 mRNA levels compared with women above the median (161 vs. 132 counts; P = 0.04; one-sided Mann-Whitney U test). There was no significant relationship between mean metabolic equivalents of task rate or mean sedentary time and BRCA1 mRNA expression (Spearman correlation P ≥ 0.75; P ≥ 0.14; Mann-Whitney U test). These findings suggest that prolonged periods of sedentary behavior are associated with significantly lower BRCA1 mRNA expression. Whether this translates into a potentially more harmful effect in BRCA1 mutation carriers warrants further investigation.