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Implication statement: Overuse of healthcare resources is prevalent, including among medical trainees. As front-line clinicians and near-peers, residents are well-positioned to teach resource stewardship to medical students and address barriers students may face while trying to “choose wisely.” We describe the implementation of two resident-led, case-based teaching sessions for medical students that focus on resource stewardship. Similar teaching models can be adapted by residents at their own institutions to enhance resource stewardship proficiency amongst trainees.

Ovarian function suppression (OFS) benefits young women with hormone receptor (HR)-positive breast cancer but they are at risk for ovarian function breakthrough. We assessed endocrine effects of gonadotropin-releasing hormone agonist (GnRHa) treatment in a prospective cohort of patients aged ≤ 40 years with HR-positive breast cancer. Plasma estradiol (E2), estrone, and follicule-stimulating hormone (FSH) levels were measured from blood samples drawn 1 and 4 years after diagnosis. Patient characteristics, invasive breast cancer-free survival (iBCFS), and overall survival (OS) were compared between those with and without E2 > 2.72 pg/mL during GnRHa treatment. Among eligible patients, 54.7% (46/84) and 60% (15/25) had E2 > 2.72 pg/mL at 1 and 4 years, respectively. Factors associated with E2 > 2.72 pg/mL at 1 year were no prior chemotherapy (P = 0.045) and tamoxifen use (P = 0.009). After a median follow-up of 7 years, among patients with stage I-III breast cancer (N = 74), iBCFS events were seen in 6 (8.1%) with E2 > 2.72 pg/mL and 5 (6.8%) with E2 ≤ 2.72 pg/mL (P = 0.893). Among patients with de novo metastatic breast cancer (N = 12), 6 (50%) with E2 > 2.72 pg/mL and 3 (25%) with E2 ≤ 2.72 pg/mL died during follow-up (P = 0.052). Larger studies exploring the clinical implications of incomplete E2 suppression by GnRHa are needed to ensure optimal OFS treatment strategies are being employed for this population., (© 2024. The Author(s).)

Purpose of Review: In this review, the evolving role of currently available genomic assays for hormone receptor-positive, early-stage breast cancer in the selection of patients for extended adjuvant endocrine therapy will be discussed., Recent Findings: Several studies have investigated the prognostic performance of the Oncotype DX, Breast Cancer Index (BCI), Prosigna, and EndoPredict genomic assays in the late recurrence setting (>5 years after diagnosis), beyond standardly used clinicopathologic parameters, with mixed results. Recently, BCI has also been validated to predict the likelihood of benefit from extended endocrine therapy, though certain data limitations may need to be addressed to justify routine use in clinical practice., Summary: Even after 5 years of adjuvant endocrine therapy, patients with hormone receptor-positive breast cancer have a significant risk for late recurrence, including distant metastases, that might be prevented with longer durations of endocrine therapy. However, the added toxicity and variable benefit derived from extended endocrine therapy make optimal patient selection crucial. Genomic assays are in development to risk-stratify patients for late recurrence and determine efficacy of extended endocrine therapy, with the aim to help guide extended endocrine therapy decisions for clinicians and individualize treatment strategies for patients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ductal carcinoma in situ (DCIS) is uncommon and understudied in young women. The objective of this study is to describe clinicopathologic features, treatment, and oncologic outcomes in a modern cohort of women aged ≤ 40 years with DCIS., Patients and Methods: Patients with DCIS were identified from the Young Women's Breast Cancer Study, a multisite prospective cohort of women diagnosed with stage 0-IV breast cancer at age ≤ 40 years, enrolled from 2006 to 2016. Clinical data were collected from patient surveys and medical records. Pathologic features were examined by central review. Data were summarized with descriptive statistics and groups were compared with χ 2 and Fisher's exact tests., Results: Among the 98 patients included, median age of diagnosis was 38 years; 36 (37%) patients were symptomatic on presentation. DCIS nuclear grade was high in 35%, intermediate in 50%, and low in 15% of lesions; 36% of lesions had comedonecrosis. The majority of patients underwent bilateral mastectomy (57%), 16 (16%) underwent unilateral mastectomy, and 26 (27%) underwent lumpectomy, most of whom received radiation. Few (13%) patients were receiving tamoxifen therapy 1 year postdiagnosis. Over a median follow-up of 8.4 years, six patients (6%) had disease recurrence, including five locoregional and one distant event., Conclusions: A high proportion of young women with DCIS underwent mastectomy with or without contralateral prophylactic mastectomy. Although DCIS was frequently symptomatic on presentation and exhibited unfavorable pathologic factors, clinicopathologic features were overall heterogeneous and few recurrences occurred. This underscores the need for careful consideration of treatment options in young women with DCIS., (© 2022. Society of Surgical Oncology.)

Purpose: To assess the impact of fertility preservation (FP) requiring ovarian stimulation on breast cancer outcomes and pregnancy after breast cancer., Methods: Women aged ≤ 40 years diagnosed with stage I-III breast cancer between 2007 and 2018 and referred for FP consultation prior to systemic therapy were identified from a British Columbia fertility center database. The primary endpoint was invasive breast cancer-free survival (iBCFS) and secondary endpoints were overall survival (OS) and achievement of pregnancy. Survival and pregnancy endpoints were compared using Cox and logistic regression analyses, respectively, for patients who did and did not undergo FP., Results: The study included 153 patients, with 71 (46%) in the FP group and 82 (54%) in the non-FP group. Patients who underwent FP were more likely to be ECOG 0 (99% vs. 88%, p = 0.011) and receive chemotherapy (93% vs. 67%, p < 0.001), but had similar ER positivity status to non-FP patients (70% vs. 79%, p = 0.21). Over a median follow-up of 4.1 years, there were no differences in iBCFS (HR 1.006, 95% CI 0.416-2.438, p = 0.988) or OS (HR 0.789, 95% CI 0.210-2.956, p = 0.725) between FP and non-FP groups. Patients who underwent FP had higher odds of conceiving at least once (OR 3.024, 95% CI 1.312-6.970, p = 0.008)., Conclusion: At a median follow-up of 4.1 years, FP did not impact iBCFS or OS, supporting its safety in young women with breast cancer. In addition, patients who underwent FP were more likely to become pregnant after breast cancer, highlighting the value of pre-oncologic treatment FP in survivorship family planning., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Advances in cancer medicines have resulted in tangible health impacts, but the magnitude of benefits of approved cancer medicines could vary greatly. Health Technology Assessment (HTA) is a multidisciplinary process used to inform resource allocation through a systematic value assessment of health technology. This paper reviews the challenges in conducting HTA for cancer medicines arising from oncology trial designs and uncertainties of safety-efficacy data., Methods: Multiple databases (PubMed, Scopus and Google Scholar) and grey literature (public health agencies and governmental reports) were searched to inform this policy narrative review., Results: A lack of robust efficacy-safety data from clinical trials and other relevant sources of evidence has made HTA for cancer medicines challenging. The approval of cancer medicines through expedited pathways has increased in recent years, in which surrogate endpoints or biomarkers for patient selection have been widely used. Using these surrogate endpoints has created uncertainties in translating surrogate measures into patient-centric clinically (survival and quality of life) and economically (cost-effectiveness and budget impact) meaningful outcomes, with potential effects on diverting scarce health resources to low-value or detrimental interventions. Potential solutions include policy harmonization between regulatory and HTA authorities, commitment to generating robust post-marketing efficacy-safety data, managing uncertainties through risk-sharing agreements, and using value frameworks., Conclusion: A lack of robust efficacy-safety data is a central problem for conducting HTA of cancer medicines, potentially resulting in misinformed resource allocation.

Although breast cancer is rare and understudied in adults age 40 and younger, recent epidemiologic data show an increasing incidence of breast cancer among young women in the United States and ongoing inferior long-term outcomes. Given breast cancers arising at a young age are more likely to present at advanced stages and to have aggressive biology, multimodal treatments are often indicated. Elevated local recurrence risks and greater propensity for germline cancer predisposition mutations can impact local therapy choices. Recently, escalated systemic therapy regimens for triple-negative breast cancer incorporating immunotherapy, de-escalated anti-HER2 therapy, and emerging targeted agents, including CDK4/6 inhibitors and PARP inhibitors, for early-stage disease may be employed in younger and older patients alike, with some special considerations. Prognostic genomic signatures can spare low-risk young women with hormone receptor-positive breast cancer adjuvant chemotherapy, but management of intermediate-risk patients remains controversial. Ovarian function suppression and extended endocrine therapy are improving outcomes in hormone receptor-positive breast cancer, but treatment adherence is a particular problem for young patients. Young women may also face greater challenges in long-term survivorship, including impaired fertility, difficulties in psychosocial adjustment, and other treatment-related comorbidities. Consideration of these age-specific issues through dedicated multidisciplinary strategies is necessary for optimal care of young women with breast cancer.

Background: The trial assigning individualized options for treatment (Rx) (TAILORx) confirmed the predictive value of the 21-gene recurrence score (RS) assay in hormone receptor (HR)-positive, HER2-negative, node-negative breast cancer and established thresholds for chemotherapy benefit in younger and older patients. Real-world chemotherapy use and RS-guided treatment costs in British Columbia post-TAILORx were examined., Methods: The authors assembled 3 cohorts of HR-positive, HER2-negative, node-negative patients with breast cancer defined by diagnosis: before RS funding (cohort 1 [C1]: January 2013-December 2013), after introduction of public RS funding (cohort 2 [C2]: July 2015-June 2016), and after TAILORx results (cohort 3 [C3]: July 2018-June 2019). Chemotherapy use was compared between cohorts by age and RS. Budgetary impacts of RS testing on chemotherapy costs were evaluated pre- and post-TAILORx., Results: Among the 2066 patients included, chemotherapy use declined by 19% after RS funding was introduced and by an additional 23% after TAILORx publication (P = .001). Reduction in chemotherapy use was significant for RS 11-20 tumors (C3 vs C2, P = .004). There was no significant change in chemotherapy use in patients >50 years old (C2:12% vs C3:10%, P = .22). RS testing was associated with higher cost savings post-TAILORx, except in patients 70 to 80 years old, where testing led to excess costs when adjusting for the low rate of RS-concordant chemotherapy prescribed., Conclusions: TAILORx has had population-based impacts on chemotherapy prescribing in intermediate RS tumors and patients ≤50 years old. The lower clinical use of RS and increased spending in patients 70-80 years old highlights the importance of careful selection of older candidates for high-cost genomic testing., Lay Summary: The 21-gene recurrence score (RS) test helps predict whether patients with hormone-positive, HER2-negative, lymph node-negative breast cancer are likely to benefit from chemotherapy. The recent trial assigning individualized options for treatment (Rx) (TAILORx) found that patients with intermediate RS tumors did not benefit from chemotherapy. The authors assessed whether TAILORx results translated to real-world changes in chemotherapy prescribing patterns. In this study, chemotherapy use decreased by 23% after TAILORx, with the greatest reductions seen among intermediate RS tumors and younger patients. In contrast, RS testing had lower clinical value and increased treatment costs in elderly patients, which requires further study to ensure optimal care for this age group., (© 2021 American Cancer Society.)

Purpose: Data exploring optimal sequencing of anthracyclines and taxanes as neoadjuvant chemotherapy (NACT) for breast cancer are limited and inconsistent. The objective of this study was to assess the real-world impact of sequence order on pathologic complete response (pCR) and clinical outcomes from NACT., Methods: Patients with HER2-negative breast cancer treated with NACT from May 2012 to April 2020 were identified from a prospectively collected institutional database. The primary endpoint was to compare rates of pCR (ypT0/isN0) between patients who received anthracyclines followed by taxanes (AC-T) to those who received taxanes followed by anthracyclines (T-AC). Additional endpoints of interest included clinical complete response, downstaging, Neo-Bioscore, conversion to breast-conserving surgery eligibility, relapse-free survival, and overall survival between groups., Results: Of the 283 patients who met eligibility criteria, 187 (66%) received AC-T and 96 (34%) received T-AC. Sequence order did not influence the primary endpoint of pCR rate (19% for AC-T vs. 21% for T-AC, p = 0.752). There were also no significant differences in secondary NACT efficacy outcomes between groups. In the overall cohort, pCR rate was higher in patients with triple-negative breast cancer (TNBC) (32% vs. 13% in hormone-positive cancer, p < 0.001) and grade 3 tumors (31% vs. 12% for grade 1-2 tumors, p < 0.001)., Conclusions: In this real-world analysis of HER2-negative breast cancer patients, there was no differential impact on pCR rate or clinical outcomes from NACT with sequence order of anthracyclines and taxanes. This supports the current variation in prescribing practice.

Approximately 20% of all breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). Targeting breast cancer through this vital oncogenic protein has been a major step towards improved patient outcomes. Today, several anti-HER2 agents are in clinical use including: the monoclonal antibodies trastuzumab and pertuzumab; the small molecule inhibitors lapatinib, neratinib, and tucatinib; and the antibody-drug conjugates ado-trastuzumab emtansine and trastuzumab deruxtecan, in some jurisdictions. In addition, several trastuzumab biosimilars have recently been granted regulatory approval in North America and the EU, and are enhancing patient access to HER2-directed therapy. The various agents differ greatly in their side-effect profiles and approved indications, from neoadjuvant and adjuvant use in early disease, to first- and later-line use in metastatic disease. This review discusses the current treatment recommendations for the use of anti-HER2 agents alone and in combination, examines the latest advances in HER2-targeted drugs and how they may be best applied in clinical practice, and provides guidance on optimal sequencing of the growing array of therapeutic options for HER2-positive breast cancer.

Germline pathogenic variants in the BRCA1-associated protein-1 ( BAP1 ) gene cause the BAP1 tumor predisposition syndrome (TPDS). BAP1 TPDS is associated with an increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes. Here, we report a germline nonsense BAP1 variant (c.850G>T, p.Glu284Ter) in a patient with bladder cancer and a strong family history of malignancy. Concurrently, we identified a somatic frameshift BAP1 variant, and as expected, immunostaining validated the loss of BAP1 protein in patient-derived tumor specimens. Together, these data provide strong evidence of pathogenicity in this case. With the addition of bladder cancer to the tumor types reported with germline BAP1 mutations, our understanding of the BAP1 TPDS continues to evolve, and may affect future screening and surveillance guidelines., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)