Hereditary Breast Cancer: BRCA Mutations and Beyond.

Hereditary breast cancers are manifested by pathogenic and likely pathogenic genetic mutations. Penetrance expresses the breast cancer risk associated with these genetic mutations. Although BRCA1/2 are the most widely known genetic mutations associated with breast cancer, numerous additional genes demonstrate high and moderate penetrance for breast cancer. This review describes current genetic testing, details the specific high and moderate penetrance genes for breast cancer and reviews the current approach to screening for breast cancer in patients with these genetic mutations.

Facilitating Culturally Competent Breast Imaging Care in South Asian Patients.

South Asians are a rapidly growing subset of the Asian population in the United States. They comprise people from multiple countries with diverse beliefs, languages, and cultural identities and values. The incidence of breast cancer is rising in South Asian women in the United States, with earlier onset and predilection for HER2-enriched tumors. Despite the rising incidence of breast cancer, participation in screening remains lower than other populations. Health care inequities in South Asian women are multifactorial and may be due to traditional health beliefs and practices, language barriers, cultural differences, and lack of overall awareness. Developing a culturally sensitive environment in breast imaging clinic practice can lead to improved patient care and adherence. Given the scarcity of data specific to the South Asian population in United States, there is a need for health service researchers and practice leaders to obtain more high-quality data to understand the needs of South Asian patient populations.

Multimodality Imaging of Benign and Malignant Diseases of the Nipple-Areolar Complex.

The nipple-areolar complex (NAC), a unique anatomic structure of the breast, encompasses the terminal intramammary ducts and skin appendages. Several benign and malignant diseases can arise within the NAC. As several conditions have overlapping symptoms and imaging findings, understanding the distinctive nipple anatomy, as well as the clinical and imaging features of each NAC disease process, is essential. A multimodality imaging approach is optimal in the presence or absence of clinical symptoms. The authors review the ductal anatomy and anomalies, including congenital abnormalities and nipple retraction. They then discuss the causes of nipple discharge and highlight best practices for the imaging workup of pathologic nipple discharge, a common condition that can pose a diagnostic challenge and may be the presenting symptom of breast cancer. The imaging modalities used to evaluate and differentiate benign conditions (eg, dermatologic conditions, epidermal inclusion cyst, mammary ductal ectasia, periductal mastitis, and nonpuerperal abscess), benign tumors (eg, papilloma, nipple adenoma, and syringomatous tumor of the nipple), and malignant conditions (eg, breast cancer and Paget disease of the breast) are reviewed. Breast MRI is the current preferred imaging modality used to evaluate for NAC involvement by breast cancer and select suitable candidates for nipple-sparing mastectomy. Different biopsy techniques (US -guided biopsy and stereotactic biopsy) for sampling NAC masses and calcifications are described. This multimodality imaging approach ensures an accurate diagnosis, enabling optimal clinical management and patient outcomes. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Diffusion Tensor Imaging for Characterizing Changes in Triple-Negative Breast Cancer During Neoadjuvant Systemic Therapy.

BACKGROUND: Assessment of treatment response in triple-negative breast cancer (TNBC) may guide individualized care for improved patient outcomes. Diffusion tensor imaging (DTI) measures tissue anisotropy and could be useful for characterizing changes in the tumors and adjacent fibroglandular tissue (FGT) of TNBC patients undergoing neoadjuvant systemic treatment (NAST). PURPOSE: To evaluate the potential of DTI parameters for prediction of treatment response in TNBC patients undergoing NAST. STUDY TYPE: Prospective. POPULATION: Eighty-six women (average age: 51 ± 11 years) with biopsy-proven clinical stage I-III TNBC who underwent NAST followed by definitive surgery. 47% of patients (40/86) had pathologic complete response (pCR). FIELD STRENGTH/SEQUENCE: 3.0 T/reduced field of view single-shot echo-planar DTI sequence. ASSESSMENT: Three MRI scans were acquired longitudinally (pre-treatment, after 2 cycles of NAST, and after 4 cycles of NAST). Eleven histogram features were extracted from DTI parameter maps of tumors, a peritumoral region (PTR), and FGT in the ipsilateral breast. DTI parameters included apparent diffusion coefficients and relative diffusion anisotropies. pCR status was determined at surgery. STATISTICAL TESTS: Longitudinal changes of DTI features were tested for discrimination of pCR using Mann-Whitney U test and area under the receiver operating characteristic curve (AUC). A P value <0.05 was considered statistically significant. RESULTS: 47% of patients (40/86) had pCR. DTI parameters assessed after 2 and 4 cycles of NAST were significantly different between pCR and non-pCR patients when compared between tumors, PTRs, and FGTs. The median surface/average anisotropy of the PTR, measured after 2 and 4 cycles of NAST, increased in pCR patients and decreased in non-pCR patients (AUC: 0.78; 0.027 ± 0.043 vs. -0.017 ± 0.042 mm2 /s). DATA CONCLUSION: Quantitative DTI features from breast tumors and the peritumoral tissue may be useful for predicting the response to NAST in TNBC. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 4.

Predicting pathological complete response to neoadjuvant systemic therapy for triple-negative breast cancers using deep learning on multiparametric MRIs.

We trained and validated a deep learning model that can predict the treatment response to neoadjuvant systemic therapy (NAST) for patients with triple negative breast cancer (TNBC). Dynamic contrast enhanced (DCE) MRI and diffusion-weighted imaging (DWI) of the pre-treatment (baseline) and after four cycles (C4) of doxorubicin/cyclophosphamide treatment were used as inputs to the model for prediction of pathologic complete response (pCR). Based on the standard pCR definition that includes disease status in either breast or axilla, the model achieved areas under the receiver operating characteristic curves (AUCs) of 0.96 ± 0.05, 0.78 ± 0.09, 0.88 ± 0.02, and 0.76 ± 0.03, for the training, validation, testing, and prospective testing groups, respectively. For the pCR status of breast only, the retrained model achieved prediction AUCs of 0.97 ± 0.04, 0.82 ± 0.10, 0.86 ± 0.03, and 0.83 ± 0.02, for the training, validation, testing, and prospective testing groups, respectively. Thus, the developed deep learning model is highly promising for predicting the treatment response to NAST of TNBC.Clinical Relevance- Deep learning based on serial and multiparametric MRIs can potentially distinguish TNBC patients with pCR from non-pCR at the early stage of neoadjuvant systemic therapy, potentially enabling more personalized treatment of TNBC patients.

Triple-Negative Breast Cancer: Histopathologic Features, Genomics, and Treatment.

Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive group of tumors that are defined by the absence of estrogen and progesterone receptors and lack of ERBB2 (formerly HER2 or HER2/neu) overexpression. TNBC accounts for 8%-13% of breast cancers. In addition, it accounts for a higher proportion of breast cancers in younger women compared with those in older women, and it disproportionately affects non-Hispanic Black women. TNBC has high metastatic potential, and the risk of recurrence is highest during the 5 years after it is diagnosed. TNBC exhibits benign morphologic imaging features more frequently than do other breast cancer subtypes. Mammography can be suboptimal for early detection of TNBC owing to factors that include the fast growth of this cancer, increased mammographic density in young women, and lack of the typical features of malignancy at imaging. US is superior to mammography for TNBC detection, but benign-appearing features can lead to misdiagnosis. Breast MRI is the most sensitive modality for TNBC detection. Most cases of TNBC are treated with neoadjuvant chemotherapy, followed by surgery and radiation. MRI is the modality of choice for evaluating the response to neoadjuvant chemotherapy. Survival rates for individuals with TNBC are lower than those for persons with hormone receptor-positive and human epidermal growth factor receptor 2-positive cancers. The 5-year survival rates for patients with localized, regional, and distant disease at diagnosis are 91.3%, 65.8%, and 12.0%, respectively. The early success of immunotherapy has raised hope regarding the development of personalized strategies to treat TNBC. Imaging and tumor biomarkers are likely to play a crucial role in the prediction of TNBC treatment response and TNBC patient survival in the future. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Imaging Features Following Breast Explant Surgery: A Pictorial Essay.

Breast implants can be removed with breast explantation surgery (BES) for various reasons, including patient dissatisfaction, capsular contracture, implant infection or rupture, breast implant-associated anaplastic large cell lymphoma, and a recently emerging phenomenon called breast implant illness. There is very limited data on the imaging appearance after BES. A retrospective chart review was performed for patients with BES findings on imaging reports for the period between October 2016 and October 2021. When assessing BES techniques, a key element is determining whether the implant's fibrous capsule requires removal. The second important question is if the patient requires an additional aesthetic procedure after BES. BES techniques include capsulotomy, and partial, total, or en bloc capsulectomy. Adjunctive aesthetic or reconstructive procedures after BES include fat grafting, mastopexy, augmentation, and reconstruction with flaps. The majority of post-BES breast imaging findings are related to the surgical scar/bed, thereby confirming that the type of explantation surgery is important. Imaging findings after BES include focal and global asymmetries, architectural distortions, calcifications, calcified and non-calcified fat necrosis, masses, hematomas, seromas, capsular calcifications, and silicone granulomas. Most importantly, since these patients have residual breast tissue, paying attention to imaging features that are suspicious for breast cancer is necessary.

Molecular Breast Imaging and Positron Emission Mammography.

There is growing interest in application of functional imaging modalities for adjunct breast imaging due to their unique ability to evaluate molecular/pathophysiologic changes, not visible by standard anatomic breast imaging. This has led to increased use of nuclear medicine dedicated breast-specific single photon and coincidence imaging systems for multiple indications, such as supplemental screening, staging of newly diagnosed breast cancer, evaluation of response to neoadjuvant treatment, diagnosis of local disease recurrence in the breast, and problem solving. Studies show that these systems maybe especially useful for specific subsets of patients, not well served by available anatomic breast imaging modalities.

Assessment of Response to Neoadjuvant Systemic Treatment in Triple-Negative Breast Cancer Using Functional Tumor Volumes from Longitudinal Dynamic Contrast-Enhanced MRI.

Early assessment of neoadjuvant systemic therapy (NAST) response for triple-negative breast cancer (TNBC) is critical for patient care in order to avoid the unnecessary toxicity of an ineffective treatment. We assessed functional tumor volumes (FTVs) from dynamic contrast-enhanced (DCE) MRI after 2 cycles (C2) and 4 cycles (C4) of NAST as predictors of response in TNBC. A group of 100 patients with stage I-III TNBC who underwent DCE MRI at baseline, C2, and C4 were included in this study. Tumors were segmented on DCE images of 1 min and 2.5 min post-injection. FTVs were measured using the optimized percentage enhancement (PE) and signal enhancement ratio (SER) thresholds. The Mann-Whitney test was used to compare the performance of the FTVs at C2 and C4. Of the 100 patients, 49 (49%) had a pathologic complete response (pCR) and 51 (51%) had a non-pCR. The maximum area under the receiving operating characteristic curve (AUC) for predicting the treatment response was 0.84 (p < 0.001) for FTV at C4 followed by FTV at C2 (AUC = 0.82, p < 0.001). The FTV measured at baseline was not able to discriminate pCR from non-pCR. FTVs measured on DCE MRI at C2, as well as at C4, of NAST can potentially predict pCR and non-pCR in TNBC patients.

Prediction of pathologic complete response to neoadjuvant systemic therapy in triple negative breast cancer using deep learning on multiparametric MRI.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Neoadjuvant systemic therapy (NAST) followed by surgery are currently standard of care for TNBC with 50-60% of patients achieving pathologic complete response (pCR). We investigated ability of deep learning (DL) on dynamic contrast enhanced (DCE) MRI and diffusion weighted imaging acquired early during NAST to predict TNBC patients' pCR status in the breast. During the development phase using the images of 130 TNBC patients, the DL model achieved areas under the receiver operating characteristic curves (AUCs) of 0.97 ± 0.04 and 0.82 ± 0.10 for the training and the validation, respectively. The model achieved an AUC of 0.86 ± 0.03 when evaluated in the independent testing group of 32 patients. In an additional prospective blinded testing group of 48 patients, the model achieved an AUC of 0.83 ± 0.02. These results demonstrated that DL based on multiparametric MRI can potentially differentiate TNBC patients with pCR or non-pCR in the breast early during NAST.

Breast Angiosarcoma: Imaging Features With Histopathologic Correlation.

Breast angiosarcoma is a rare malignancy of endothelial origin that can be categorized as primary angiosarcoma (PAS) or secondary angiosarcoma (SAS) based on etiology. Primary angiosarcoma typically affects younger women with no known risk factors, whereas SAS of the breast typically develops in older women who have undergone breast cancer treatment. There are two types of SAS, one that develops in the setting of chronic lymphedema and one that develops as a radiation-associated neoplasm after breast-conserving therapy (BCT). Clinically, PAS often presents as a palpable mass that may be rapidly growing, whereas SAS presents with skin changes such as erythematous plaques or nodules or with areas of skin discoloration. Mammographically, the appearance of PAS can be nonspecific and may be obscured by the dense tissue that is characteristic of the young patient population it typically affects. Cases of mammographically occult PAS have been visible at US and MRI. Mammography and US have been found to be less sensitive than MRI for the diagnosis of secondary radiation-associated angiosarcoma. Angiosarcomas, both PAS and SAS, are graded, depending on degree of differentiation, as low, intermediate, or high grade. Endothelial markers such as ERG and CD31 immunohistochemical stains are used to support the diagnosis of angiosarcomas. In this article, we review the clinical presentation, imaging findings, associated histopathology, and treatment of primary and secondary breast angiosarcoma.

The Post-Operative Mammographic Appearance of Lymphovenous Bypass and Vascularized Lymph Node Transfer.

The postoperative mammographic imaging appearance related to lymphovenous bypass and vascularized lymph node transfer has not been described. It is important for breast imagers to become familiar with the expected appearance of surgical changes that can be seen in the follow up imaging of breast cancer survivors in order to create accurate reports and adjust imaging protocols to improve imaging quality and lessen patient discomfort as needed.

BI-RADS Ultrasound Lexicon Descriptors and Stromal Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer.

PURPOSE: Increased levels of stromal tumor-infiltrating lymphocytes (sTILs) have recently been considered a favorable independent prognostic and predictive biomarker in triple-negative breast cancer (TNBC). The purpose of this study was to determine the relationship between BI-RADS (Breast Imaging Reporting and Data System) ultrasound lexicon descriptors and sTILs in TNBC. MATERIALS AND METHODS: Patients with stage I-III TNBC were evaluated within a single-institution neoadjuvant clinical trial. Two fellowship-trained breast radiologists used the BI-RADS ultrasound lexicon to assess pretreatment tumor shape, margin, echo pattern, orientation, posterior features, and vascularity. sTILs were defined as low <20 or high ≥20 on the pretreatment biopsy. Fisher's exact tests were used to assess the association between lexicon descriptors and sTIL levels. RESULTS: The 284 patients (mean age 52 years, range 24-79 years) were comprised of 68% (193/284) with low-sTIL tumors and 32% (91/284) with high-sTIL tumors. TNBC tumors with high sTILs were more likely to have the following features: (1) oval/round shape than irregular shape (p = 0.003), (2) circumscribed or microlobulated margins than spiculated, indistinct, or angular margins (p = 0.0005); (3) complex cystic and solid pattern than heterogeneous pattern (p = 0.006); and (4) posterior enhancement than shadowing (p = 0.002). There was no significant association between sTILs and descriptors for orientation and vascularity (p = 0.06 and p = 0.49, respectively). CONCLUSION: BI-RADS ultrasound descriptors of the pretreatment appearance of a TNBC tumor can be useful in discriminating between tumors with low and high sTIL levels. Therefore, there is a potential use of ultrasound tumor characteristics to complement sTILs when used as stratification factors in treatment algorithms for TNBC.

Education of Radiologists in Healthcare Disparities.

Disparities exist in access to a multitude of screening and diagnostic imaging examinations and procedures. To address these disparities within radiology, emphasis so far has been placed upon diversifying the workforce and formally educating trainees on healthcare disparities. Currently, there is no organized and nationally accepted educational program or content for practicing radiologists specific to diversity and healthcare disparity. This void can be addressed by providing an educational curriculum framework for practicing radiologists based on three key factors: individual efforts, calling for institutional change, and national collaboration. Individual efforts should focus on acknowledging the existence of disparities, understanding the contribution of one's implicit bias in perpetuating disparities, understanding and highlighting issues related to insurance coverage of radiology examinations, and participating in radiology political action committees. These efforts can be facilitated by a consolidated web-based training program for practicing radiologists. To pave the way for meaningful systemic change, the implementation of institutional change like that initiated by the Culture of Safety movement in 2002 is needed. A national collaborative effort initiated by radiology organizations to empower radiologists and recognize positive changes would further provide support. SUMMARY: A three-pronged educational framework combining individual radiologist education, institutional change, and national collaboration will enable radiologists to play a role in addressing imaging-related disparities in healthcare.

Team Science: A Practical Approach to Starting Collaborative Projects.

A collaborative approach to treating patients is well taught in medical training. However, collaboration and team building in clinical and laboratory research may have been given less emphasis. More scientific discoveries are now being made with multidisciplinary teams, requiring a thoughtful approach in order to achieve research goals while mitigating potential conflicts. Specific steps for a successful team science project include building the team, assigning roles and responsibilities, allocating rules, and discussing authorship guidelines. Building a team involves bringing individuals together and developing a common research goal while establishing psychological safety for all members of the team. Clear assignment of roles and responsibilities avoids confusion and allows each member's contributions to be acknowledged. Allocating rules involves discussing how decisions in the team will be made, how data and knowledge sharing will occur, and how potential conflicts will be resolved. Discussing authorship at the start of the project ensures that the entire team knows what work must be completed for authorship to be obtained.

Baseline FDG PET-CT imaging is necessary for newly diagnosed inflammatory breast cancer patients: a narrative review.

OBJECTIVE: To review and discuss the rationale behind performing baseline 18-fluorodeoxyglucose positron emission tomography-computed tomography imaging for staging of inflammatory breast cancer patients. BACKGROUND: In the past three decades, the epidemiology of inflammatory breast cancer has resulted in separation of this entity from other breast cancer in staging and treatment. Advances in cancer imaging from 18-fluorodeoxyglucose positron emission tomography to 18-fluorodeoxyglucose positron emission tomography-computed tomography have now allowed for anatomic and functional correlation in evaluating extent of disease in cancer patients. Furthermore, studies throughout the past two decades have highlighted how 18-fluorodeoxyglucose positron emission tomography-computed tomography may play a role in staging inflammatory breast cancer patients given the uniqueness of this entity when compared to other breast cancers. METHODS: Narrative overview of the literature summarizing findings in the literature from searches in computerized databases and authoritative texts. The use of 18-fluorodeoxyglucose positron emission tomography-computed tomography with respect to regional nodal staging and distant metastasis detection in inflammatory breast cancer patients is reviewed. In addition, an overview of studies conducted to date comparing the sensitivity and specificity of 18-fluorodeoxyglucose positron emission tomography-computed tomography for baseline staging in inflammatory breast cancer patients is also provided. Therapeutic influences and effect on overall survival is discussed. CONCLUSIONS: Baseline 18-fluorodeoxyglucose positron emission tomography-computed tomography allows for more optimal nodal staging, which has implications in prognosis and treatment of inflammatory breast cancer patients. It also allows for improved detection of metastasis on baseline presentation allowing therapy to potentially target these additional sites of disease.

Transitioning to Practice: Getting up to Speed in Efficiency and Accuracy.

The transition from trainee to breast radiologist is challenging. The many new responsibilities that breast radiologists acquire while establishing themselves as clinicians may increase stress and anxiety. Taking inventory of existing knowledge and skills and addressing deficits toward the end of one's training can be beneficial. New breast radiologists should expect to be slower and gain proficiency in the first several years out of training. Having realistic expectations for oneself with respect to screening mammography interpretation and following up on the subsequent diagnostic imaging workup of screening callback examinations can increase competence and confidence. Familiarity with the available literature to guide management in the diagnostic setting can increase efficiency. Planning ahead for localizations and biopsies also allows for efficiency while alleviating anxiety. Ultimately, adapting to a new work environment using a collaborative approach with primary healthcare providers, pathologists, and surgeons while remembering to have mentors within and beyond the field of radiology allows for a more successful transition.

Time to development and imaging features of new calcifications in the treated breast after breast-conserving therapy.

OBJECTIVE: The purpose of our study was to analyze the time to development, malignancy rate, location, and mammographic features of new calcifications in the treated breast after breast-conserving therapy (BCT). MATERIALS AND METHODS: In this HIPAA-complaint, IRB-approved retrospective study, we reviewed the records of patients treated with BCT at our institution with breast-conserving surgery performed between January 1, 2009 and December 31, 2010. A total of 735 breasts in 732 women were included in our study cohort. Factors analyzed included rate of development of new calcifications, malignancy rate of new calcifications, the time between completion of radiation therapy and development of new calcifications, imaging features of new calcifications, and location of the new calcifications in relation to the primary malignancy. RESULTS: During follow-up, new calcifications developed in 155 of the 735 treated breasts (21.1%) and 155 of the 732 women (21.2%). After excluding two cases that were lost to follow-up, the malignancy rate of new calcifications was 5.2% (8/153; 95% CI: 2.3% to 10.0%). The median time to development of the benign calcifications was 27 months (range, 2 to 91 months) and of the malignant calcifications was 41 months (range, 11 to 57 months). Of the 20 (13.1%) cases of new calcifications categorized as BI-RADS 3 (probably benign), all were benign on follow-up (19 cases) or on biopsy (1 case). Of the 51 BI-RADS 4 (suspicious) cases, 8 (16%) were biopsy-proven malignant. The malignancy rate was the highest in fine pleomorphic 100% (1/1), followed by amorphous 17%, (5/29), coarse heterogeneous 8% (2/26) and typically benign 0 (0/97) calcifications (p < 0.0001). The malignancy rate was 1.5% (2/137) for new calcifications within the lumpectomy site vs. 37.5% (6/16) for new calcifications outside the lumpectomy site (p < 0.0001) and was 3.4% (5/147) for new calcifications at or within the same quadrant as the lumpectomy site vs. 50.0% (3/6) for new calcifications in a different quadrant from the lumpectomy site (p=0.002). CONCLUSION: Most new calcifications that developed in the treated breast after BCT were benign. Evaluation of morphology and distribution of those calcifications is imperative. New calcifications in the treated breast outside the lumpectomy site are more likely to be malignant and should be viewed with greater suspicion. Benign calcifications developed earlier than malignant calcifications, but the time courses overlapped.

Patient Diversity in Breast Imaging: Barriers and Potential Solutions.

Recent reports have highlighted disparities in breast cancer care related to patient diversity. Breast radiologists represent the face of breast imaging and are key players in advocating for patients to reduce these disparities. Diversity-related barriers for breast imaging patients, as they journey from screening to survivorship, include impediments to access and quality of care, gaps in communication, and lack of knowledge in both providers and patients. Potential strategies for overcoming these specific barriers include "culturally tailored" nurse navigators, mobile mammography, improved communication, patient and provider education, and breast radiologist involvement in advocacy efforts promoting diversity. As current trends in recommendations and guidelines for breast imaging include more numerous and advanced imaging modalities, it is important to acknowledge and address diversity-related disparities.

Efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal patients with metastatic, hormone receptor-positive, HER2-negative breast cancer: a phase II study.

Background Increased adiposity is thought to result in worse clinical outcomes in patients with breast cancer through increased estrogen production, hyperinsulinemia, insulin resistance, and activation of the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. Thus, we hypothesized that the addition of metformin to everolimus and exemestane, could lead to better outcomes in overweight and obese patients with metastatic, hormone receptor-positive, HER2-negative breast cancer. We conducted a phase II trial to evaluate the efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal women with metastatic, hormone receptor-positive, HER2-negative breast cancer. Methods Twenty-two patients with a body mass index ≥25 kg/m2 were treated with metformin 1000 mg twice daily, everolimus 10 mg daily and exemestane 25 mg daily. Median progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results Median PFS and OS were 6.3 months (95% confidence interval [CI]: 3.8-11.3 months) and 28.8 months (95% CI: 17.5-59.7 months), respectively. Five patients had a partial response and 7 had stable disease for ≥24 weeks yielding a clinical benefit rate of 54.5%. Compared with overweight patients, obese patients had an improved PFS on univariable (p = 0.015) but not multivariable analysis (p = 0.215). Thirty-two percent of patients experienced a grade 3 treatment-related adverse event (TRAE). There were no grade 4 TRAEs and 7 patients experienced a grade 3 TRAE. Conclusion The combination of metformin, everolimus and exemestane was safe and had moderate clinical benefit in overweight and obese with patients metastatic, hormone receptor-positive, HER2-negative breast cancer.