Date of Award

January 2025

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Maryam Lustberg

Abstract

Breast cancer (BC) is a heterogeneous disease, with multiple subtypes based on receptor status, tumor histology type, stage at diagnosis, and other variables, all of which influence treatment decisions that are considered by oncologists and patients. The purpose of the studies presented in this thesis is to explore two different important questions in breast cancer - adjuvant bisphosphonate prescribing patterns in early-stage breast cancer (EBC), and multimodality curative-intent treatment vs palliative therapy in de novo oligometastatic BC – in order to gain further insight into management decision-making and guideline implementation. The first study aims to understand prescribing patterns of bone-modifying agents (BMAs), bisphosphonates and denosumab, in EBC. Based on improved survival, the 2017 American Society of Clinical Oncology (ASCO) and Cancer Care Ontario clinical guidelines (ACGD) recommended consideration of adjuvant bisphosphonates for postmenopausal women with early-stage breast cancer (EBC). However, small survey-based studies suggest inconsistent prescribing. This study evaluated receipt of adjuvant BMAs in the United States (US) before and after publication of the 2017 ACGD, as well as the variables that may be associated with BMA receipt. We conducted a retrospective cohort study using the nationwide Flatiron Health electronic health record-derived de-identified database, with a cohort of EBC patients diagnosed between 2012-2019, to compare the proportion of patients receiving adjuvant BMAs pre- and post-ACGD and identify factors associated with receipt of all BMAs and of bisphosphonates alone. In our cohort of 11,470 patients, those diagnosed post-ACGD (2017-19) were more likely to receive adjuvant BMAs (9%) than patients diagnosed in earlier years (7.4%; OR 1.23; 95% confidence interval (CI) 1.08-1.42; p=0.002). Among BMA recipients, 65.8% received denosumab only, 32.6% received bisphosphonates only, and 1.4% received both. Post-menopausal status, age ≥50, receipt of adjuvant chemotherapy and endocrine therapy, and coexisting bone loss diagnoses were significantly associated with increased receipt of adjuvant BMAs. This retrospective cohort study revealed overall low prescribing of adjuvant BMAs for patients diagnosed with EBC, with only a modest increase in prescribing following the publication of the 2017 ASCO/CCO clinical guidelines, and most patients who received BMAs received denosumab, not bisphosphonates. The updated 2022 ASCO/CCO guidelines continue to endorse bisphosphonate use in the adjuvant setting, and there continues to be a need for improved implementation and dissemination of recent guidelines in clinical practice. Further studies should also aim to understand the specific reasons why EBC patients and their oncologists might or might not consider including bisphosphonates as part of adjuvant treatment. The second study presented here explores treatment decisions in de novo oligometastatic breast cancer (oligo-mBC), a unique subset of patients for whom best management practices have been controversial in the breast oncology community. Retrospective studies have suggested that patients with de novo oligo-mBC may have a better prognosis when compared to recurrent metastatic cancers. Current guidelines do not differentiate between de novo oligo-mBC and all metastatic BC due to limited clinical trial data in this population, and standard of care in the US is to treat palliatively, although optimal management remains uncertain. We present a survey of 193 US medical oncologists regarding their management decisions when treating de novo oligo-mBC patients. The survey was conducted via the ASCO Survey Pool. The survey instrument asked 7 demographic questions, 1 insurance question, and 4 questions focused on treatment preferences for de novo oligo-mBC management, repeated 3 times for each receptor subtype – Estrogen Receptor Positive (ER+), Human Epidermal Growth Factor Receptor 2 Positive (HER2+), and Triple Negative disease. Our results indicate varied practice patterns in de novo oligo-mBC. The majority of respondents recommend initial palliative chemotherapy, however if a patient shows a positive response to initial chemotherapy, a substantial amount of respondents (42-54%) recommend ablative radiation of all residual lesions, and 38-52% recommend surgical resection of the primary tumor. The results varied by receptor subtype, with the highest percentage of respondents recommending curative-intent therapies in HER2+ disease, although these differences were not statistically significant. Additionally, 57.3% of respondents reported that their de novo oligo-mBC patients “sometimes” or “often” experience insurance coverage issues when prescribed multimodality treatment. This study highlights the need for future randomized clinical trials to investigate if survival benefit could be gained from a multimodality approach in de novo oligometastatic breast cancer. Furthermore, additional research should be conducted to explore if specific patient or provider factors are associated with a higher likelihood of preferring multimodality vs palliative treatment plans.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 05/14/2027

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