Nipple-Sparing Mastectomy and Adequate Margins for Patients With Ductal Carcinoma In Situ.

BACKGROUND: For patients with ductal carcinoma in situ (DCIS) undergoing breast conservation surgery (BCS), guidelines advise a margin width of at least 2 mm, with studies demonstrating decreased recurrence risk compared to narrower margins. However, limited data exist establishing if this margin is appropriate in mastectomies, and specifically for nipple-sparing mastectomy (NSM). Consequently, we evaluated the margins of DCIS patients undergoing NSM and resulting oncologic outcomes. METHODS: A single-institution retrospective review was performed in patients with DCIS or DCIS with microinvasion (DCIS + MI) undergoing NSM from April 2010 to December 2021. Patient and tumor characteristics, margin status, treatment, and outcomes information were collected. The association between margins and local-regional (LRR) and distant recurrence (DR) were examined. RESULTS: 161 patients were included, comprising 284 NSM (164 therapeutic, 120 prophylactic). 153 patients had DCIS and 8 had DCIS + MI. Most patients had hormone sensitive, 123 (76.4%), and nuclear grade 2, 72 (44.7%), disease. In total, 35 (21.7%) patients had positive or <2 mm margins. Of these, 21 (60%) involved the anterior margin. At a median follow-up of 45 months (range 0-151), 2.5% (n = 4) had a LRR and .6% (n = 1) had a DR. Of patients with a recurrence, only 2 had positive or <2 mm margins, 1 had received endocrine therapy, and none received adjuvant radiation. DISCUSSION: No specific margin status was found to correlate with recurrence for patients with DCIS or DCIS + MI undergoing NSM, with an altogether low recurrence risk. Overall, this suggests that recommended DCIS margins in BCS doesn't necessarily apply in NSM, where margins of <2 mm may be acceptable.

Lumpectomy without radiation for ductal carcinoma in situ of the breast: 20-year results from the ECOG-ACRIN E5194 study.

We report the 20-year rate of ipsilateral breast event (IBE) for patients with ductal carcinoma in situ (DCIS) treated with lumpectomy without radiation on a non-randomized prospective clinical trial. Patients were enrolled in cohort 1: low- or intermediate-grade DCIS, size ≤ 2.5 cm (n = 561); or cohort 2: high-grade DCIS, size ≤ 1 cm (n = 104). The Kaplan-Meier method was used to estimate time-to-event distributions. Cox proportional hazard methods were used to estimate hazard ratios (HRs) and tests for significance for event times. 561 patients were enrolled in cohort 1 and 104 in cohort 2. After central pathology review, 26% in cohort 1 were recategorized as high-grade and 26% in cohort 2 as low- or intermediate-grade. Mean DCIS size was similar at 7.5 mm in cohort 1 and 7.8 mm in cohort 2. Surgical margin was ≥3 mm in 96% of patients, and about 30% received tamoxifen. Median follow-up was 19.2 years. There were 104 IBEs, of which 54 (52%) were invasive. The IBE and invasive IBE rates increased in both cohorts up to 15 years, then plateaued. The 20-year IBE rates were 17.8% for cohort 1 and 28.7% for cohort 2 (p = 0.005), respectively. Invasive IBE occurred in 9.8% and 15.1% (p = 0.09), respectively. On multivariable analysis, IBE risk increased with size and was higher in cohort 2, but grade and margin width were not significantly associated with IBE. For patients with DCIS treated with excision without radiation, the rate of IBE increased with size and assigned cohort mostly in the first 15 years.

Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials: NeoSTEEP.

PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS: The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS: The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION: End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.

Positive Nipple Margins and Oncologic Outcomes of Nipple-Sparing Mastectomy in a Large Community-Based Hospital System.

The American Society of Breast Surgeons recommends sending separate nipple margins (NMs) when performing nipple-sparing mastectomies (NSMs). However, the definition of a positive NM is vague. We evaluated NM management and outcomes in breast cancer patients undergoing NSM from 2010 to 2021 at our community-based hospital system through a retrospective review and descriptive analysis. A total of 619 patients (1086 NSM) were included. Median invasive tumor size was 1.5cm and median follow-up 30 months. Fourteen therapeutic NSMs had tumor within the NMs. Nine were positive using the definition "any tumor within the separate NM," and nipple-areolar complex (NAC) excised. Two were negative when positive was defined as "any tumor on ink," and were observed without recurrence. Our results suggest positive NMs warranting NAC excision could be interpreted as "any tumor on ink" and NSMs can be safely performed with low rates of positive NMs and recurrences in high-volume hospitals.

Factors Associated With Breast Cancer Surgery Delay Within a Coordinated Multihospital Community Health System: When Does Surgical Delay Impact Outcome?

BACKGROUND: Multiple factors influence the time elapsed between diagnosis of breast cancer and surgical extirpation of the primary tumor. The disease-free interval between resection of primary breast cancer and first evidence of recurrence is predictive of mortality. We aimed to determine patient, disease, and treatment factors associated with a delay in time to surgery (TTS) and identify the point when prolonged TTS negatively impacts disease-free survival. PATIENTS AND METHODS: Cancer registry and electronic medical record data for patients with breast cancer who underwent surgery as first course of treatment during 2006-2016 were retrospectively reviewed. Patients undergoing surgery in ≤30 vs. 31-60 vs. >60 days of initial diagnosis were compared. Kaplan-Meier survival analyses with Cox proportional hazards were performed to evaluate impact of time from breast cancer diagnosis to definitive therapeutic surgery on breast cancer recurrence or death (all-cause). RESULTS: Overall, 4462 patients were analyzed, 43.4% of whom underwent surgery beyond 30 days. The following factors were associated with TTS >30 days: age <50, non-Hispanic White race/ethnicity, commercial or health exchange/Medicaid insurance, diagnosis of noninvasive disease (i.e., ductal carcinoma in situ), had breast magnetic resonance imaging before definitive surgery, underwent total mastectomy (especially if immediate reconstruction, particularly if autologous, was performed), and did not receive adjuvant therapies (P < .001 for all). After adjusting for relevant variables, significant predictors of recurrence/death included a TTS >60 days, increased patient age, higher breast cancer stage, and triple-negative biomarker expression. CONCLUSION: Risk of recurrence or death is not compromised until TTS exceeds 60 days after initial breast cancer diagnosis.

Breast MRI in the setting of DCIS: quality trials are still needed to determine its value.

KEY POINTS: • Existing evidence suggests that preoperative breast MRI does not improve treatment outcomes for DCIS. • The quality of the available data used to answer this question is poor. • Quality randomized controlled trials are needed to definitively assess the benefits and harms of preoperative MRI in the setting of DCIS.

Breast cancer recurrence risk after hormonal contraceptive use in survivors of reproductive age.

OBJECTIVE: To assess the risk of recurrence with hormonal contraceptive use in breast cancer survivors of reproductive age. STUDY DESIGN: In this retrospective study, women ages 18-51 years who were diagnosed with primary stage 0-3 breast cancer between 2006-2016 and subsequently entered remission were included. Patients with missing information within the cancer registry or electronic medical record and those with a history of hysterectomy and/or sterilization procedure prior to diagnosis were excluded. Hormonal contraception use was defined as being prescribed an oral contraceptive pill (OCP), patch, vaginal ring, medroxyprogesterone injection, etonogestrel implant, or levonorgestrel-releasing intrauterine device (IUD). Women were separated into two groups, hormonal contraceptive users and non-users. Basic descriptive and inferential statistics were used to compare groups as appropriate. The primary outcome reviewed was local or distant breast cancer recurrence. Secondary outcomes included all-cause mortality and pregnancy. RESULTS: Following exclusions, 1370 women remained in the cohort. Ninety-seven women (7.08 %) received a prescription for a form of hormonal contraception. When comparing groups, hormonal contraceptive users were more likely to be between 18-40 years of age (46.39 % vs. 17.99 % non-users;P < 0.01) and never smokers (68.04 % vs. 38.57 % non-users; P < 0.01). Patients did not differ between groups based on any other demographic or cancer-related characteristic, including tumor hormone receptor expression. Overall, 92 patients (6.72 %) experienced local or distant recurrence during the study period. Recurrence did not differ between groups (6.19 % users vs. 6.76 % non-users; P = 0.83). All-cause mortality and pregnancy rates also did not differ between hormonal contraceptive users and non-users. CONCLUSION: The study shows no increased risk of recurrence associated with hormonal contraceptive use after breast cancer diagnosis and remission.

Team triathlon effects on physiological, psychological, and immunological measures in women breast cancer survivors.

PURPOSE: Exercise after breast cancer diagnosis and treatment improves cancer-related outcomes, although the mechanisms involved are not clear. This study evaluated the impact of exercise on body composition, strength, endurance, quality of life (QOL), fatigue, and endocrine and inflammatory biomarkers in breast cancer survivors participating in a highly monitored, clinically supervised, moderate-intensity exercise program. The association of hormonal and inflammatory biomarkers with the observed physiological changes was assessed. METHODS: Female breast cancer survivors (BCS; n = 46) who engaged in a goal-oriented 14-week triathlon exercise training program were compared to an untrained control group of female BCS (n = 16). Psychosocial metrics, QOL, cancer-related fatigue, and exercise self-efficacy were evaluated via pre- and post-exercise intervention questionnaires. Serum estradiol and inflammatory biomarkers (C-reactive protein (CRP), sTNFR1a, estradiol, leptin, and adiponectin) were measured prior to the exercise training program start and after the completion of the goal triathlon. RESULTS: After exercise training, the exercise group had lower BMI and arm circumferences. Greater positive change was noted in the trained group for QOL, fatigue, and self-efficacy questionnaires. Functional endurance improved in the trained but not the control group. Knee and elbow strength were not different between the groups, except that knee flexion at 180 degrees∙sec-1 was higher in trained. The only significantly different biomarker was adiponectin, which decreased in the trained group. CONCLUSIONS: Group triathlon exercise training may be beneficial to BCS by significantly improving their psychosocial measures, functional endurance, and BMI.

WEE1 inhibitor, AZD1775, overcomes trastuzumab resistance by targeting cancer stem-like properties in HER2-positive breast cancer.

Although trastuzumab has greatly improved the outcome of HER2-positive breast cancer, the emergence of resistance hampers its clinical benefits. Trastuzumab resistance is a multi-factorial consequence predominantly due to presence of cancer stem-like cells (CSCs). AZD1775, a potent anti-cancer agent targeting WEE1 kinase to drive tumor cells with DNA damage to premature mitosis, has previously shown high efficacies when targeting different cancers with a well-tolerated cytotoxic profile, but has not been evaluated in trastuzumab-resistant (TrR) breast cancer. We sought to investigate the effect of AZD1775 on cancer stem-like cell (CSC) properties, apoptosis, cell cycle regulation in TrR breast cancer. Our study for the first time demonstrated that AZD1775 induces apoptosis and arrests TrR cells at G2/M phase. More importantly, AZD1775 effectively targeted CSC properties by suppressing MUC1 expression levels. AZD1775 administration also induced apoptosis in our in-house patient-derived tumor cell line at passage 0, implying its significant clinical relevance. These findings highlight the potential clinical application of AZD1775 in overcoming trastuzumab resistance in breast cancer.

Promoting Team-Based Exercise Among African American Breast Cancer Survivors.

Physical activity benefits the health and well-being of breast cancer survivors (BCS). Yet, many African American survivors do not routinely exercise and have increased risk of poor outcomes. The purpose of this mixed-method study was to identify motivational factors compelling African American BCS to participate in a 14-week team walking program and to intend to continue exercise after the intervention concluded. Focus groups were held with participants ( n = 12) before and after training. Content analysis discovered themes before the intervention: Not wanting to go at it alone, exercise not a life or treatment priority, cancer treatment affected activity, advocates to exercise, and can exercise really help? Four themes postintervention themes included: In the same boat, changed mind-set, improved weight and activity, and overcoming barriers. Physical data verified improvements. Results suggest that a team-based exercise training program may assist in overcoming a sedentary behavior tendency and subsequently improve health among survivors.

The American Society of Breast Surgeons and Quality Payment Programs: Ranking, Defining, and Benchmarking More Than 1 Million Patient Quality Measure Encounters.

BACKGROUND: To identify and remediate gaps in the quality of surgical care, the American Society of Breast Surgeons (ASBrS) developed surgeon-specific quality measures (QMs), built a patient registry, and nominated itself to become a Center for Medicare and Medicaid Services (CMS) Qualified Clinical Data Registry (QCDR), thereby linking surgical performance to potential reimbursement and public reporting. This report provides a summary of the program development. METHODS: Using a modified Delphi process, more than 100 measures of care quality were ranked. In compliance with CMS rules, selected QMs were specified with inclusion, exclusion, and exception criteria, then incorporated into an electronic patient registry. After surgeons entered QM data into the registry, the ASBrS provided real-time peer performance comparisons. RESULTS: After ranking, 9 of 144 measures of quality were chosen, submitted, and subsequently accepted by CMS as a QCDR in 2014. The measures selected were diagnosis of cancer by needle biopsy, surgical-site infection, mastectomy reoperation rate, and appropriateness of specimen imaging, intraoperative specimen orientation, sentinel node use, hereditary assessment, antibiotic choice, and antibiotic duration. More than 1 million patient-measure encounters were captured from 2010 to 2015. Benchmarking functionality with peer performance comparison was successful. In 2016, the ASBrS provided public transparency on its website for the 2015 performance reported by our surgeon participants. CONCLUSIONS: In an effort to improve quality of care and to participate in CMS quality payment programs, the ASBrS defined QMs, tracked compliance, provided benchmarking, and reported breast-specific QMs to the public.

Triathlon training for women breast cancer survivors: feasibility and initial efficacy.

ᅟ: Exercise can improve quality of life (QOL) in breast cancer survivors. In contrast to many group or home-based exercise programs, little is known about the effectiveness of goal-oriented recreational activities. PURPOSE: The purpose of this study was to evaluate a clinically overseen team triathlon training program on improving physiological and psychosocial health-related measures in female breast cancer survivors. METHODS: Twenty-three participants (age = 48 (8), BMI = 25 (1), mean (SE)) were recruited from a 14-week sprint triathlon (800-m swim, 20-km bike, 5-km run) team training program for women breast cancer survivors (4 (3) years post-surgery, chemo-, or radiation-therapy). Training included two supervised group and three home-based individual sessions per week. Pre- and post-training outcomes included isokinetic knee extensor strength (60, 180, and 300° s-1), 6-min walk test (6MWT), maximal oxygen uptake (VO2 max), QOL (Functional Assessment of Cancer Therapy -Breast (FACT-B)), and barriers to exercise. Outcomes were also obtained 6 months post except for VO2 max. Significance was set at p < 0.05. RESULTS: Data are mean (SD) from 21 complete data sets. Knee extensor peak torque significantly improved only at 300° s-1 (pre 40.3(8.5) ftlb; post 45.2(8.4); p = 0.001). 6MWT significantly improved (pre 632.8(62.1) m; post 657.4(53.2); p = 0.014) as did VO2 max (pre 31.3(5.8) ml kg-1 min-1; post 35.9(5.8); p < 0.001). FACT-B also improved (pre 114(12); post 122(13); p = 0.004), including the FACT-G total score, social well-being, and breast cancer subscales while barriers to exercise decreased (pre 54(12); post 36(9); p < 0.001). Strength, 6MWT, and barriers to exercise remained improved after 6 months. CONCLUSIONS: Team triathlon training in breast cancer survivors can increase aerobic capacity and improve QOL which may contribute to healthier lifestyles in breast cancer survivors.

NK cell-mediated antibody-dependent cellular cytotoxicity is enhanced by tamoxifen in HER2/neu non-amplified, but not HER2/neu-amplified, breast cancer cells.

Tumor-targeting antibodies have been successful in the treatment of various types of cancers. Antibodies engage the immune system with their Fc, stimulating immune cell effector function. In the clinic, FcγRIIIa polymorphisms with higher affinity for the Fc of antibodies were shown to improve response rates and overall survival. Efforts have been made to modify the Fc to enhance affinity to Fc receptors and thereby improve effector function. An alternative for improving immune effector function may be to increase the level of tumor antigen expression. In this study, tamoxifen was used to increase HER2/neu protein level to determine whether increased tumor antigen expression could enhance NK cell-mediated antibody-dependent cytotoxicity (ADCC). Tamoxifen was found to increase HER2/neu 1.5-fold to threefold in breast cancer cell lines that were HER2/neu non-amplified. Using flow cytometry to simultaneously evaluate NK cell degranulation and tumor cell death, the increase in HER2/neu enhanced NK cell-mediated ADCC. However, in cells that had HER2/neu gene amplification and estrogen receptor expression, tamoxifen elevated HER2/neu but failed to improve NK cell function. The quantity of HER2/neu on the tumor cell surface was approximately double that of the number of Fc receptors found on NK cells. This appears to reflect a ceiling at which increasing antigen expression fails to improve NK cell effector function. This has clinical implications as trying to increase antigen expression to enhance NK cell function may be useful for patients with antigen-low tumors, but not in those whose tumors have gene amplification or high levels of antigen expression.

Measures of Appropriateness and Value for Breast Surgeons and Their Patients: The American Society of Breast Surgeons Choosing Wisely (®) Initiative.

BACKGROUND: Current breast cancer care is based on high-level evidence from randomized, controlled trials. Despite these data, there continues to be variability of breast cancer care, including overutilization of some tests and operations. To reduce overutilization, the American Board of Internal Medicine Choosing Wisely (®) Campaign recommends that professional organizations provide patients and providers with a list of care practices that may not be necessary. Shared decision making regarding these services is encouraged. METHODS: The Patient Safety and Quality Committee of the American Society of Breast Surgeons (ASBrS) solicited candidate measures for the Choosing Wisely (®) Campaign. The resulting list of "appropriateness" measures of care was ranked by a modified Delphi appropriateness methodology. The highest-ranked measures were submitted to and later approved by the ASBrS Board of Directors. They are listed below. RESULTS: (1) Don't routinely order breast magnetic resonance imaging in new breast cancer patients. (2) Don't routinely excise all the lymph nodes beneath the arm in patients having lumpectomy for breast cancer. (3) Don't routinely order specialized tumor gene testing in all new breast cancer patients. (4) Don't routinely reoperate on patients with invasive cancer if the cancer is close to the edge of the excised lumpectomy tissue. (5) Don't routinely perform a double mastectomy in patients who have a single breast with cancer. CONCLUSIONS: The ASBrS list for the Choosing Wisely (®) campaign is easily accessible to breast cancer patients online. These measures provide surgeons and their patients with a starting point for shared decision making regarding potentially unnecessary testing and operations.

Survivors speak: a qualitative analysis of motivational factors influencing breast cancer survivors' participation in a sprint distance triathlon.

AIMS AND OBJECTIVES: To examine motivational factors influencing breast cancer survivors to participate in triathlon training, complete a triathlon and maintain an exercise thereafter. BACKGROUND: Routine exercise has been shown to improve quality of life and reduce recurrence for breast cancer survivors. Yet physical and psychological factors present barriers for initiating and maintaining an exercise routine. Research is limited in exploring factors of exercise motivation from the survivor's perspective. DESIGN: Qualitative design using focus groups and individual follow-up phone interviews to explore motivation for exercise initiation and maintenance. METHODS: One to two weeks after completing a triathlon, 11 breast cancer survivors who trained together participated in one of three focus groups to discuss their experience. Five months post triathlon 6 of the 11 participants were successfully contacted and phone interviews were conducted to explore exercise maintenance. Focus groups and interviews were analysed using content and thematic analysis. RESULTS: Five themes emerged (1) Champion for Exercise, (2) Part of a Team, (3) Everyone Had a Story, (4) Not Really Exercise and (5) What Do We Do Now? Overall, survivors recognised their need for lifestyle change (e.g. moving from a sedentary lifestyle to a more active one). More importantly, they identified the team approach to exercise initiation was crucial in their success in sustaining a behavioural change. CONCLUSIONS: Emphasis needed on developing team exercise training programmes for survivors. Nurses can play a critical role in discussing with survivors, the benefits of exercise initiation and maintenance. RELEVANCE TO CLINICAL PRACTICE: Breast cancer survivors are hesitant to initiate routine exercise. Training with women who share a common lived experience increases the likelihood of success. Nurses are in a position to encourage breast cancer survivors to participate in group exercise programmes as a way to improve quality of life.

Improving Quality Metric Adherence to Minimally Invasive Breast Biopsy among Surgeons Within a Multihospital Health Care System.

BACKGROUND: Minimally invasive breast biopsy (MIBB) is the procedure of choice for diagnosing breast lesions indeterminate for malignancy. Multihospital health care systems face challenges achieving systemwide adherence to standardized guidelines among surgeons with varying practice patterns. This study tested whether providing individual feedback about surgeons' use of MIBB to diagnose breast malignancies improved quality metric adherence across a large health care organization. STUDY DESIGN: We conducted a prospective matched-pairs study to test differences (or lack of agreement) between periods before and after intervention. All analytical cases of primary breast cancer diagnosed during 2011 (period 1) and from July 2012 to June 2013 (period 2) across a multihospital health care system were reviewed for initial diagnosis by MIBB or open surgical biopsy. Open surgical biopsy was considered appropriate care only if MIBB could not be performed for reasons listed in the American Society of Breast Surgeons' quality measure for preoperative diagnosis of breast cancer. Individual and systemwide results of adherence to the MIBB metric during period 1 were sent to each surgeon in June 2012 and were later compared with period 2 results using McNemar's test of marginal homogeneity for matched binary responses. RESULTS: Forty-six surgeons were evaluated on use of MIBB to diagnose breast cancer. In period 1, metric adherence for 100% of cases was achieved by 37 surgeons, for a systemwide 100% compliance rate of 80.4%. After notification of individual performance, 44 of 46 surgeons used MIBB solely or otherwise appropriate care to diagnose breast cancer, which improved systemwide compliance to 95.7%. CONCLUSIONS: Providing individual and systemwide performance results to surgeons can increase self-awareness of practice patterns when diagnosing breast cancer, leading to standardized best-practice care across a large health care organization.

Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics.

A wealth of evidence has now demonstrated that the microenvironment in which a tumorigenic cell evolves is as critical to its evolution as the genetic mutations it accrues. However, there is still relatively little known about how signals from the microenvironment contribute to the early events in the progression to malignancy. To address this question, we used a premalignant mammary model to examine how fibroblasts, and the extracellular matrix (ECM) proteins they secrete, influence progression to malignancy. Their effect on metastatic malignant cells was also assessed for comparison. We found that carcinoma-associated fibroblasts, and the distinct aligned ECM they deposit, can cause both premalignant and malignant mammary epithelial cells to assume a mesenchymal morphology that is associated with increased dissemination and metastasis, while benign reduction mammoplasty fibroblasts favor the maintenance of an epithelial morphology and constrain early dissemination, tumor growth, and metastasis. Our results suggest that normalizing the organization of the ECM could be effective in limiting systemic dissemination and tumor growth.

CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues.

UNLABELLED: Although high mammographic density is considered one of the strongest risk factors for invasive breast cancer, the genes involved in modulating this clinical feature are unknown. Tissues of high mammographic density share key histologic features with stromal components within malignant lesions of tumor tissues, specifically low adipocyte and high extracellular matrix (ECM) content. We show that CD36, a transmembrane receptor that coordinately modulates multiple protumorigenic phenotypes, including adipocyte differentiation, angiogenesis, cell-ECM interactions, and immune signaling, is greatly repressed in multiple cell types of disease-free stroma associated with high mammographic density and tumor stroma. Using both in vitro and in vivo assays, we show that CD36 repression is necessary and sufficient to recapitulate the above-mentioned phenotypes observed in high mammographic density and tumor tissues. Consistent with a functional role for this coordinated program in tumorigenesis, we observe that clinical outcomes are strongly associated with CD36 expression. SIGNIFICANCE: CD36 simultaneously controls adipocyte content and matrix accumulation and is coordinately repressed in multiple cell types within tumor and high mammographic density stroma, suggesting that activation of this stromal program is an early event in tumorigenesis. Levels of CD36 and extent of mammographic density are both modifiable factors that provide potential for intervention.