The Canadian Breast Cancer Symposium 2023 Meeting Report.

On 15-16 June 2023, healthcare professionals and breast cancer patients and advocates from across Canada met in Toronto, Ontario, for the 2023 Canadian Breast Cancer Symposium (CBSC.). The CBSC. is a national, multidisciplinary event that occurs every 2 years with the goal of developing a personalized approach to the management of breast cancer in Canada. Experts provided state-of-the-art information to help optimally manage breast cancer patients, including etiology, prevention, diagnosis, experimental biology, and therapy of breast cancer and premalignant breast disease. The symposium also had the objectives of increasing communication and collaboration among breast cancer healthcare providers nationwide and providing a comprehensive and real-life review of the many facets of breast cancer. The sessions covered the patient voice, the top breast cancer papers from different disciplines in 2022, artificial intelligence in breast cancer, systemic therapy updates, the management of central nervous system metastases, multidisciplinary management of ductal carcinoma in situ, special populations, optimization-based individual prognostic factors, toxicity management of novel therapeutics, survivorship, and updates in surgical oncology. The key takeaways of these sessions have been summarized in this conference report.

Optimizing Postneoadjuvant Treatment in Patients With Early Breast Cancer Achieving Pathologic Complete Response.

pCR should be integrated with other prognostic factors to optimize postneoadjuvant treatments in BC.

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer.

Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. Exposure: TIL abundance in breast tissue from resected primary tumors. Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

Ribociclib plus Endocrine Therapy in Early Breast Cancer.

BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).

Breast Cancer Index and Prediction of Extended Aromatase Inhibitor Therapy Benefit in Hormone Receptor-positive Breast Cancer from the NRG Oncology/NSABP B-42 Trial.

PURPOSE: BCI (H/I) has been shown to predict extended endocrine therapy (EET) benefit. We examined BCI (H/I) for EET benefit prediction in NSABP B-42, which evaluated extended letrozole therapy (ELT) in hormone receptor-positive breast cancer patients after 5 years of ET. METHODS: Stratified Cox model was used to analyze RFI as primary endpoint, with DR, BCFI, and DFS, as secondary endpoints. Due to a non-proportional effect of ELT on DR, time-dependent analyses were performed. RESULTS: The translational cohort included 2,178 patients (45% BCI (H/I)-High, 55% BCI (H/I)-Low). ELT showed an absolute 10-year RFI benefit of 1.6% (P=0.10), resulting in an underpowered primary analysis (50% power). ELT benefit and BCI (H/I) did not show a significant interaction for RFI (BCI [(H/I])-Low: 10y absolute benefit 1.1% [HR=0.70, 0.43-1.12, P=0.13]; BCI [(H/I])-High: 2.4% [HR=0.83, 0.55-1.26, p=0.38]; Pinteraction=0.56). Time-dependent DR analysis showed that after 4y, BCI (H/I)-High patients had significant ELT benefit (HR=0.29, 0.12-0.69, P<0.01), whereas BCI (H/I)-Low patients were less likely to benefit (HR=0.68, 0.33-1.39, P=0.29) (Pinteraction=0.14). Prediction of ELT benefit by BCI (H/I) was more apparent in the HER2- subset after 4y (ELT-by-BCI (H/I) Pinteraction=0.04). CONCLUSIONS: BCI(H/I)-High vs -Low did not show a statistically significant difference in ELT benefit for the primary endpoint (RFI). However, in time-dependent DR analysis, BCI (H/I)-High patients experienced statistically significant benefit from ELT after 4y, whereas (H/I)-Low patients did not. Because BCI (H/I) has been validated as a predictive marker of EET benefit in other trials, additional follow-up may enable further characterization of BCI's predictive ability.

Managing the Risk of Lung Toxicity with Trastuzumab Deruxtecan (T-DXd): A Canadian Perspective.

Ongoing advances in precision cancer therapy have increased the number of molecularly targeted and immuno-oncology agents for a variety of cancers, many of which have been associated with a risk of pulmonary complications, among the most concerning being drug-induced interstitial lung disease/pneumonitis (DI-ILD). As the number of patients undergoing treatment with novel anticancer agents continues to grow, DI-ILD is expected to become an increasingly significant clinical challenge. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2 that is gaining widespread use in the metastatic breast cancer setting and is undergoing exploration for other oncologic indications. ILD/pneumonitis is an adverse event of special interest associated with T-DXd, which has potentially fatal consequences if left untreated and allowed to progress. When identified in the asymptomatic stage (grade 1), T-DXd-related ILD can be monitored and treated effectively with the possibility of treatment continuation. Delayed diagnosis and/or treatment, however, results in progression to grade 2 or higher toxicity and necessitates immediate and permanent discontinuation of this active agent. Strategies are, therefore, needed to optimize careful monitoring during treatment to ensure patient safety and optimize outcomes. Several guidance documents have been developed regarding strategies for the early identification and management of T-DXd-related ILD, although none have been within the context of the Canadian health care environment. A Canadian multidisciplinary steering committee was, therefore, convened to evaluate existing recommendations and adapt them for application in Canada. A multidisciplinary approach involving collaboration among medical oncologists, radiologists, respirologists, and allied health care professionals is needed to ensure the proactive identification and management of T-DXd-related ILD and DI-ILD associated with other agents with a similar toxicity profile.

Current Challenges and Disparities in the Delivery of Equitable Breast Cancer Care in Canada.

Recent exciting advances in the diagnosis and management of breast cancer have improved outcomes for Canadians diagnosed and living with breast cancer. However, the reach of this progress has been uneven; disparities in accessing care across Canada are increasingly being recognized and are at risk of broadening. Members of racial minority groups, economically disadvantaged individuals, or those who live in rural or remote communities have consistently been shown to experience greater challenges in accessing 'state of the art' cancer care. The Canadian context also presents unique challenges-vast geography and provincial jurisdiction of the delivery of cancer care and drug funding create significant interprovincial differences in the patient experience. In this commentary, we review the core concepts of health equity, barriers to equitable delivery of breast cancer care, populations at risk, and recommendations for the advancement of health equity in the Canadian cancer system.

Sequencing of Endocrine and Targeted Therapies in Hormone-Sensitive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Optimizing the selection and sequencing of endocrine and targeted therapies for hormone-sensitive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer is a rapidly evolving field owing in large part to an increasing pace of drug development coupled with a greater understanding of the genomic drivers of breast cancer. The recently published results from the MAINTAIN clinical trial begin to answer an important question in this patient population-can the well-established benefit with first-line cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors be stretched further by continuing this drug class beyond progression and selecting an alternate endocrine therapy partner? We present a case of a patient with hormone-sensitive HER2 low metastatic breast cancer who underwent circulating tumor DNA next-generation sequencing to better inform her treatment options after progression on first-line therapy with a CDK 4/6 inhibitor and aromatase inhibitor. Our clinical approach in this patient population prioritizes the identification of actionable mutations with high-quality evidence for efficacy on the basis of clinical trials post-CDK 4/6 inhibitors, while balancing comorbidities and patient priorities for care. Several recent clinical trials discussed herein present clinically meaningful results linking emerging targeted therapies to actionable alterations in PIK3CA, ESR1, AKT1, and PTEN. Continued drug development in this space delays time to treatment with chemotherapy, and hopefully contributes to maintaining a high quality of life for these patients on primarily oral-based therapy.

Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer.

Background: Ribociclib has demonstrated a statistically significant overall survival benefit in pre- and postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced breast cancer. New Adjuvant Trial with Ribociclib [LEE011] (NATALEE) is a trial evaluating the efficacy and safety of adjuvant ribociclib plus endocrine therapy (ET) versus ET alone in patients with HR+/HER2- early nonmetastatic breast cancer (EBC). Methods/design: NATALEE is a multicenter, randomized, open-label, Phase III trial in patients with HR+/HER2- EBC. Eligible patients include women, regardless of menopausal status, and men aged ⩾18 years. Select patients with stage IIA, stage IIB, or stage III disease (per the anatomic classification in the AJCC Cancer Staging Manual, 8th edition) with an initial diagnosis ⩽18 months prior to randomization are eligible. Patients receiving standard (neo)adjuvant ET are eligible if treatment was initiated ⩽12 months before randomization. Patients undergo 1:1 randomization to ribociclib 400 mg/day (3 weeks on/1 week off) +ET (letrozole 2.5 mg/day or anastrozole 1 mg/day [investigator's discretion] plus goserelin [men or premenopausal women]) or ET alone. Ribociclib treatment duration is 36 months; ET treatment duration is ⩾60 months. The primary end point is invasive disease-free survival. Discussion: The 36-month treatment duration of ribociclib in NATALEE is extended compared with that in other adjuvant cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor trials and is intended to maximize efficacy due to longer duration of CDK4/6 inhibition. Compared with the 600-mg/day dose used in advanced breast cancer, the reduced ribociclib dose used in NATALEE may improve tolerability while maintaining efficacy. NATALEE includes the broadest population of patients with HR+/HER2- EBC of any Phase III trial currently evaluating adjuvant CDK4/6 inhibitor treatment. Trial registration: ClinicalTrials.gov identifier: NCT03701334 (https://clinicaltrials.gov/ct2/show/NCT03701334).

Ten-year update: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-42 randomized trial: extended letrozole therapy in early-stage breast cancer.

BACKGROUND: The National Surgical Adjuvant Breast and Bowel Project B-42 trial evaluated extended letrozole therapy (ELT) in postmenopausal breast cancer patients who were disease free after 5 years of aromatase inhibitor (AI)-based therapy. Seven-year results demonstrated a nonstatistically significant trend in disease-free survival (DFS) in favor of ELT. We present 10-year outcome results. METHODS: In this double-blind, phase III trial, patients with stage I-IIIA hormone receptor-positive breast cancer, disease free after 5 years of an AI or tamoxifen followed by an AI, were randomly assigned to 5 years of letrozole or placebo. Primary endpoint was DFS, defined as time from random assignment to breast cancer recurrence, second primary malignancy, or death. All statistical tests are 2-sided. RESULTS: Between September 2006 and January 2010, 3966 patients were randomly assigned (letrozole: 1983; placebo: 1983). Median follow-up time for 3923 patients included in efficacy analyses was 10.3 years. There was statistically significant improvement in DFS in favor of letrozole compared with placebo (hazard ratio [HR] = 0.85, 95% confidence interval [CI] = 0.74 to 0.96; P = .01; 10-year DFS: placebo = 72.6%, letrozole = 75.9%, absolute difference = 3.3%). There was no difference in the effect of letrozole on overall survival (HR = 0.97, 95% CI = 0.82 to 1.15; P = .74). Letrozole statistically significantly reduced breast cancer-free interval events (HR = 0.75, 95% CI = 0.62 to 0.91; P = .003; absolute difference in cumulative incidence = 2.7%) and distant recurrences (HR = 0.72, 95% CI = 0.55 to 0.92; P = .01; absolute difference = 1.8%). The rates of osteoporotic fractures and arterial thrombotic events did not differ between treatment groups. CONCLUSIONS: The beneficial effect of ELT on DFS persisted at 10 years. Letrozole also improved breast cancer-free interval and distant recurrences without improving overall survival. Careful assessment of potential risks and benefits is necessary for selecting appropriate candidates for ELT.

Reply to Trudeau, M.; Fraser, B. The CADTH pCODR Expert Review Committee Process Explained. Comment on "Rayson et al. Access to Neoadjuvant Pertuzumab for HER2 Positive Breast Cancer in Canada: A Dilemma Increasingly Difficult to Explain. Curr. Oncol. 2022, 29, 9891-9895".

We appreciate the opportunity to respond to the comment [...].

Design of SERENA-6, a phase III switching trial of camizestrant in ESR1-mutant breast cancer during first-line treatment.

ESR1 mutation (ESR1m) is a frequent cause of acquired resistance to aromatase inhibitor (AI) plus cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), which is a first-line therapy for hormone-receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Camizestrant is a next-generation oral selective estrogen receptor degrader (SERD) that in a phase II study significantly improved progression-free survival (PFS) over fulvestrant (also a SERD) in ER+/HER2- ABC. SERENA-6 (NCT04964934) is a randomized, double-blind, phase III study evaluating the efficacy and safety of switching from an AI to camizestrant, while maintaining the same CDK4/6i, upon detection of ESR1m in circulating tumor DNA before clinical disease progression on first-line therapy for HR+/HER2- ABC. The aim is to treat ESR1m clones and extend the duration of control of ER-driven tumor growth, delaying the need for chemotherapy. The primary end point is PFS; secondary end points include chemotherapy-free survival, time to second progression event (PFS2), overall survival, patient-reported outcomes and safety.

Why will we perform this study? Patients with advanced breast cancer in which the cancer cells have the receptor for the hormone estrogen and/or progesterone are typically treated with an aromatase inhibitor, a hormone therapy that decreases estrogen being made in the body, together with an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), a drug that blocks the growth of cancer cells. Although cancers usually respond to treatment initially, the cancer cells eventually change, so the drug combination no longer works. For example, mutation of the estrogen receptor (referred to as ESR1m) can stop aromatase inhibitors from working. Camizestrant is an investigational drug that blocks estrogen receptors, including mutated receptors, reducing the growth and spread of cancer. Here we describe the SERENA-6 clinical trial, which is testing camizestrant as a treatment for patients with breast cancer with ESR1m. How will we perform this research? The phase III SERENA-6 trial will use blood tests to monitor if patients with breast cancer develop ESR1m while being treated with an aromatase inhibitor and a CDK4/6 inhibitor. If ESR1m is detected, yet the disease is stable, participants will be randomly assigned to either continue with the same aromatase inhibitor or switch to camizestrant while continuing with the same CDK4/6 inhibitor. The study will assess whether switching to camizestrant prolongs the time before the cancer grows, spreads or worsens. It will also assess the length of time that participants live for versus those who continue with an aromatase inhibitor. Clinical Trial Registration: NCT04964934 (ClinicalTrials.gov).

Overall survival with neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): A randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: ExteNET showed that neratinib, an irreversible pan-HER tyrosine kinase inhibitor, given for 1 year after trastuzumab-based therapy significantly improved invasive disease-free survival in women with early-stage HER2-positive breast cancer. We report the final analysis of overall survival in ExteNET. METHODS: In this international, randomised, double-blind, placebo-controlled, phase 3 trial, women aged 18 years or older with stage 1-3c (amended to stage 2-3c) HER2-positive breast cancer who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab were eligible. Patients were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year. Randomisation was stratified according to hormone receptor (HR) status (HR-positive vs. HR-negative), nodal status (0, 1-3 or 4+), and trastuzumab regimen (sequentially vs. concurrently with chemotherapy). Overall survival was analysed by intention to treat. ExteNET is registered (Clinicaltrials.gov: NCT00878709) and is complete. RESULTS: Between July 9, 2009, and October 24, 2011, 2840 women received neratinib (n = 1420) or placebo (n = 1420). After a median follow-up of 8.1 (IQR, 7.0-8.8) years, 127 patients (8.9%) in the neratinib group and 137 patients (9.6%) in the placebo group in the intention-to-treat population had died. Eight-year overall survival rates were 90.1% (95% CI 88.3-91.6) with neratinib and 90.2% (95% CI 88.4-91.7) with placebo (stratified hazard ratio 0.95; 95% CI 0.75-1.21; p = 0.6914). CONCLUSIONS: Overall survival in the extended adjuvant setting was comparable for neratinib and placebo after a median follow-up of 8.1 years in women with early-stage HER2-positive breast cancer.

The clinical impact of COVID-19 on patients with cancer in British Columbia: An observational study.

Objective: We evaluated survival outcomes for patients with cancer and COVID-19 in this population-based study. Methods: A total of 631 patients who tested positive for severe acute respiratory syndrome coronavirus 2 and were seen at BC Cancer between 03/03/2020 and 01/21/2021 were included, of whom 506 had a diagnosis of cancer and PCR-confirmed positive test for coronavirus disease 2019. Patient clinical characteristics were retrospectively reviewed and the influence of demographic data, cancer diagnosis, comorbidities, and anticancer treatment(s) on survival following severe acute respiratory syndrome coronavirus 2 infection were analyzed. Results: Age ≥65 years (Hazard Ratio [HR] 4.77, 95% Confidence Interval [CI] 2.72-8.35, P < 0.0001), those with Eastern Cooperative Oncology Group Performance Status ≥2 (HR 8.36, 95% CI 2.89-24.16, P < 0.0001), hypertension (HR 3.17, 95% CI 1.77-5.66, P < 0.0001), and metastatic/advanced stage (HR 3.70, 95% CI 1.77-7.73, P < 0.0001) were associated with worse coronavirus disease 2019 specific survival outcomes following severe acute respiratory syndrome coronavirus 2 infection. Patients with lung cancer had the highest 30-day COVID-19 specific mortality (25.0%), followed by genitourinary (18.1%), gastrointestinal (16.0%), and other cancer types (<10.0%). Patients with the highest 30-day coronavirus disease 2019 specific mortality according to treatment type were those on chemotherapy (23.0%), rituximab (22.2%), and immunotherapy (16.7%) while patients on hormonal treatments (2.2%) had better survival outcomes (P = 0.041) compared to those on other anticancer treatments. Conclusion: This study provides further evidence that patients with cancer are at increased risk of mortality from coronavirus disease 2019 and emphasizes the need for vaccination.

Access to Neoadjuvant Pertuzumab for HER2 Positive Breast Cancer in Canada: A Dilemma Increasingly Difficult to Explain.

The addition of pertuzumab to neoadjuvant trastuzumab and chemotherapy for women with early-stage, high-risk, HER2+ breast cancer has been observed to lead to higher pathologic complete response rates (pCR), and improved event-free survival compared to trastuzumab and chemotherapy alone. Based on available data, neoadjuvant pertuzumab is recommended by ESMO, ASCO, and NICE as well as by a Canadian Consensus Guideline Group. We discuss the implications for Canadian patients with HER2+ early breast cancer due to a second and final negative funding decision by the Canadian Agency for Drugs and Technologies in Health (CADTH) related to neoadjuvant pertuzumab. This decision will have adverse impacts for up to 1 in 6 women receiving neoadjuvant therapy for high-risk HER2+ breast cancer, due to suboptimal pCR rates and higher risks of invasive breast cancer recurrent events, resulting in the need for more toxic adjuvant therapy.

Accurate determination of CRISPR-mediated gene fitness in transplantable tumours.

Assessing tumour gene fitness in physiologically-relevant model systems is challenging due to biological features of in vivo tumour regeneration, including extreme variations in single cell lineage progeny. Here we develop a reproducible, quantitative approach to pooled genetic perturbation in patient-derived xenografts (PDXs), by encoding single cell output from transplanted CRISPR-transduced cells in combination with a Bayesian hierarchical model. We apply this to 181 PDX transplants from 21 breast cancer patients. We show that uncertainty in fitness estimates depends critically on the number of transplant cell clones and the variability in clone sizes. We use a pathway-directed allelic series to characterize Notch signaling, and quantify TP53 / MDM2 drug-gene conditional fitness in outlier patients. We show that fitness outlier identification can be mirrored by pharmacological perturbation. Overall, we demonstrate that the gene fitness landscape in breast PDXs is dominated by inter-patient differences.

Identification of Mollusc Remains (Bivalve and Gastropod) from Archaeological Sites in Semporna, Sabah.

This paper discusses the identification of mollusc (bivalve and gastropod) remains from three archaeological sites in Semporna, Sabah, namely Bukit Tengkorak, Melanta Tutup and Bukit Kamiri, dated to the prehistoric period, from 3,000 to 800 years ago. Samples of mollusc remains used in this study were obtained from a series of archaeological excavations conducted at these three sites by the Centre for Global Archaeological Research, Universiti Sains Malaysia (CGAR, USM), Penang in collaboration with the Sabah Museum Department (SMD) from 1994 to 2007. In total, 90 taxa of molluscan species, of which 30 are bivalves and 60 are gastropods, had been identified. Out of 90, there were 55 taxa identified to the species level, of which 18 are bivalves and 37 are gastropods. They consisted mainly of marine species with small numbers of freshwater, brackish and terrestrial species. This study had provided new data and insights into the distribution and exploitation of molluscs by ancient human societies in different environments in Semporna, which will be useful not only for malacological research in the tropics but also for future biological and environmental studies in Sabah, Malaysia as well as for the Southeast Asian and Pacific regions.

Current and New Novel Combination Treatments for Metastatic Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) has a worse prognosis and remains the most challenging breast cancer subtype to treat. This is largely related to the heterogeneity of this disease and the lack of reliable oncological targets. In this review, we discuss the current standard-of-care treatment options for metastatic TNBC, including recent advances with the use of immunotherapy, PARP inhibitors and antibody-drug conjugates. This review also explores new agents and novel combinations arising in the field for the treatment of advanced TNBC.

Clinical Utility of Genomic Assay in Node-Positive Early-Stage Breast Cancer.

Breast cancer (BC) is the most common malignancy among women in Canada. Adjuvant treatment in early BC can reduce the risk of BC recurrence. Historically, the decision for adjuvant chemotherapy for early BC was made only based on clinical and tumour characteristics. In recent years, there has been an effort toward developing genomic assays as a predictive and prognostic tool to improve precision in estimating disease recurrence, sensitivity to systemic treatment and ultimately with clinical utility for guidance regarding adjuvant systemic treatment(s). There are various commercial genomic tests available for early-stage ER+/HER-2 negative BC. This paper will review the Oncotype DX 21-gene Recurrence Score (RS), MammaPrint, EndoPredict, Prosigna®, and Breast Cancer Index (BCI) genomic assays. We will also focus on these genomic assays' clinical application and utility in node-positive early-stage BC based on the most recent evidence and guidance recommendations.

Proteomic analysis of archival breast cancer clinical specimens identifies biological subtypes with distinct survival outcomes.

Despite advances in genomic classification of breast cancer, current clinical tests and treatment decisions are commonly based on protein level information. Formalin-fixed paraffin-embedded (FFPE) tissue specimens with extended clinical outcomes are widely available. Here, we perform comprehensive proteomic profiling of 300 FFPE breast cancer surgical specimens, 75 of each PAM50 subtype, from patients diagnosed in 2008-2013 (n = 178) and 1986-1992 (n = 122) with linked clinical outcomes. These two cohorts are analyzed separately, and we quantify 4214 proteins across all 300 samples. Within the aggressive PAM50-classified basal-like cases, proteomic profiling reveals two groups with one having characteristic immune hot expression features and highly favorable survival. Her2-Enriched cases separate into heterogeneous groups differing by extracellular matrix, lipid metabolism, and immune-response features. Within 88 triple-negative breast cancers, four proteomic clusters display features of basal-immune hot, basal-immune cold, mesenchymal, and luminal with disparate survival outcomes. Our proteomic analysis characterizes the heterogeneity of breast cancer in a clinically-applicable manner, identifies potential biomarkers and therapeutic targets, and provides a resource for clinical breast cancer classification.