Association of Insulin Resistance and Higher Oncotype DX™ Recurrence Score.

BACKGROUND: Black women with breast cancer have a worse overall survival compared with White women; however, no difference in Oncotype DX™ (ODX) recurrence scores has been observed to explain this health disparity. Black women are also disproportionately affected by insulin resistance. We evaluated whether insulin resistance is associated with a higher ODX recurrence score and whether there is a difference between White and Black women to explain disparate clinical outcomes. METHODS: A subgroup analysis of patients in a multi-institutional cross-sectional study evaluating differences in insulin resistance between White and Black women was performed. Women diagnosed with a new hormone receptor-positive, HER2/neu-negative breast cancer with an ODX recurrence score were identified. Fasting blood glucose and insulin measurements were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) score, a method for assessing insulin resistance, and compared against ODX scores. RESULTS: Overall, 412 women (358 White women, 54 Black women) were identified. Compared with White women, Black women had a higher body mass index (30 vs. 26 kg/m2, p < 0.0001), higher HOMA-IR score (2.4 vs. 1.4, p = 0.004), and more high-grade tumors (30% vs. 16%, p = 0.01). There was a direct positive association with an increasing ODX score and HOMA-IR (p = 0.014). On subset analysis, this relationship was seen in White women (p = 0.005), but not in Black women (p = 0.55). CONCLUSION: In women with newly diagnosed breast cancer, increasing insulin resistance is associated with a higher recurrence score; however, this association was not present in Black women. This lack of association may be due to the small number of Black women in the cohort, or possibly a reflection of a different biological disease process of the patient's tumor.

Cryoablation Without Excision for Low-Risk Early-Stage Breast Cancer: 3-Year Interim Analysis of Ipsilateral Breast Tumor Recurrence in the ICE3 Trial.

BACKGROUND: The ICE3 trial is designed to evaluate the safety and efficacy of breast cryoablation, enabling women older than 60 years with low-risk early-stage breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks. METHODS: The ICE3 trial is a prospective, multi-center, single-arm, non-randomized trial including women age 60 years or older with unifocal, ultrasound-visible invasive ductal carcinoma size 1.5 cm or smaller and classified as low to intermediate grade, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Ipsilateral breast tumor recurrence (IBTR) at 5 years was the primary outcome. A 3-year interim analysis of IBTR was performed, and the IBTR probability was estimated using the Kaplan-Meier method. RESULTS: Full eligibility for the study was met by 194 patients, who received successful cryoablation per protocol. The mean age was 75 years (range, 55-94 years). The mean tumor length was 8.1 mm (range, 8-14.9 mm), and the mean tumor width was 7.4 mm (range, 2.8-14 mm). During a mean follow-up period of 34.83 months, the IBTR rate was 2.06% (4/194 patients). Device-related adverse events were reported as mild in 18.4% and moderate in 2.4% of the patients. No severe device-related adverse events were reported. More than 95% of the patients and 98% of the physicians reported satisfaction with the cosmetic results at the clinical follow-up evaluation. CONCLUSIONS: Breast cryoablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Further study within a clinical trial or registry is needed to confirm cryoablation as a viable alternative to surgical excision for appropriately selected low-risk patients.

Insulin resistance contributes to racial disparities in breast cancer prognosis in US women.

BACKGROUND: Racial disparities in breast cancer survival between Black and White women persist across all stages of breast cancer. The metabolic syndrome (MetS) of insulin resistance disproportionately affects more Black than White women. It has not been discerned if insulin resistance mediates the link between race and poor prognosis in breast cancer. We aimed to determine whether insulin resistance mediates in part the association between race and breast cancer prognosis, and if insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R) expression differs between tumors from Black and White women. METHODS: We conducted a cross-sectional, multi-center study across ten hospitals. Self-identified Black women and White women with newly diagnosed invasive breast cancer were recruited. The primary outcome was to determine if insulin resistance, which was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR), mediated the effect of race on prognosis using the multivariate linear mediation model. Demographic data, anthropometric measurements, and fasting blood were collected. Poor prognosis was defined as a Nottingham Prognostic Index (NPI) > 4.4. Breast cancer pathology specimens were evaluated for IR and IGF-1R expression by immunohistochemistry (IHC). RESULTS: Five hundred fifteen women were recruited (83% White, 17% Black). The MetS was more prevalent in Black women than in White women (40% vs 20%, p < 0.0001). HOMA-IR was higher in Black women than in White women (1.9 ± 1.2 vs 1.3 ± 1.4, p = 0.0005). Poor breast cancer prognosis was more prevalent in Black women than in White women (28% vs 15%. p = 0.004). HOMA-IR was positively associated with NPI score (r = 0.1, p = 0.02). The mediation model, adjusted for age, revealed that HOMA-IR significantly mediated the association between Black race and poor prognosis (ß = 0.04, 95% CI 0.005-0.009, p = 0.002). IR expression was higher in tumors from Black women than in those from White women (79% vs 52%, p = 0.004), and greater IR/IGF-1R ratio was also associated with higher NPI score (IR/IGF-1R >  1: 4.2 ± 0.8 vs IR/IGF-1R = 1: 3.9 ± 0.8 vs IR/IGF-1R < 1: 3.5 ± 1.0, p < 0.0001). CONCLUSIONS: In this multi-center, cross-sectional study of US women with newly diagnosed invasive breast cancer, insulin resistance is one factor mediating part of the association between race and poor prognosis in breast cancer.

Surgical Oncologists and the COVID-19 Pandemic: Guiding Cancer Patients Effectively through Turbulence and Change.

BACKGROUND: The COVID-19 pandemic has posed extraordinary demands from patients, providers, and health care systems. Despite this, surgical oncologists must maintain focus on providing high-quality, empathetic care for the almost 2 million patients nationally who will be diagnosed with operable cancer this year. The focus of hospitals is transitioning from initial COVID-19 preparedness activities to a more sustained approach to cancer care. METHODS: Editorial Board members provided observations of the implications of the pandemic on providing care to surgical oncology patients. RESULTS: Strategies are presented that have allowed institutions to successfully prepare for cancer care during COVID-19, as well as other strategies that will help hospitals and surgical oncologists manage anticipated challenges in the near term. Perspectives are provided on: (1) maintaining a safe environment for surgical oncology care; (2) redirecting the multidisciplinary model to guide surgical decisions; (3) harnessing telemedicine to accommodate requisite physical distancing; (4) understanding interactions between SARS CoV-2 and cancer therapy; (5) considering the ethical impact of professional guidelines for surgery prioritization; and (6) advocating for our patients who require oncologic surgery in the midst of the COVID-19 pandemic. CONCLUSIONS: Until an effective vaccine becomes available for widespread use, it is imperative that surgical oncologists remain focused on providing optimal care for our cancer patients while managing the demands that the COVID-19 pandemic will continue to impose on all of us.

Distribution of Organohalogen and Synthetic Musk Compounds in Breast Adipose Tissue of Breast Cancer Patients in Ulster County, New York, USA.

We determined the concentrations of 98 halogenated organic compounds and synthetic musks in breast fat tissues of 50 breast cancer patients (age range: 34-77 years) collected during 1996-1998 in Ulster County, New York, USA. Polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated biphenyl 153 (PBB-153), polybrominated diphenyl ethers (PBDEs), and synthetic musk compounds (SMCs) were analyzed in breast fat tissues, and 46 analytes were found at a detection frequency of ≥ 65% and at concentrations in the decreasing order of OCPs > PCBs > SMCs > PBDEs > PBB-153. PCBs (median: 323 ng/g wet wt) and dichlorodiphenyltrichloroethanes (DDTs, median: 293 ng/g wet wt) were the major compounds found in breast fat tissues. Among PCB congeners, hexa- and hepta-chlorobiphenyls (60% of total PCBs) were the abundant ones. p,p'-DDE accounted for more than 99% of the total DDT concentrations. The concentrations of SMCs and PBDEs were 1-2 orders of magnitude lower than those of PCBs and DDTs. 1,3,4,6,7,8-Hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-r-2-benzopyran (median: 33 ng/g wet wt) was the most abundant SMC, whereas BDE-47 (median: 4.5 ng/g wet wt) was the most dominant PBDE congener present in breast tissues. A significant correlation (p < 0.05) between women's age and concentrations of DDTs, chlordanes, hexachlorobenzene and PCBs in breast tissues was found. Concentrations of PCBs, PBDEs, OCPs, and SMCs were not significantly different between malignant and benign tumor cases. This study adds baseline information on target tissue burdens of persistent organic contaminants in breast cancer patients.

Society of Surgical Oncology Breast Disease Working Group Statement on Prophylactic (Risk-Reducing) Mastectomy.

Over the past several years, there has been an increasing rate of bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM) surgeries. Since publication of the 2007 SSO position statement on the use of risk-reducing mastectomy, there have been significant advances in the understanding of breast cancer biology and treatment. The purpose of this manuscript is to review the current literature as a resource to facilitate a shared and informed decision-making process regarding the use of risk-reducing mastectomy.

Clinical Experience With Mammary Ductoscopy.

BACKGROUND: Most breast cancers begin in the ductal epithelium with normal cells and progress to atypia and finally to carcinoma. Mammary ductoscopy enables one to directly visualize and sample the ductal epithelium and, therefore, identify early changes cytologically. This article describes our initial experience with mammary ductoscopy at Beth Israel Medical Center. METHODS: A prospective review of all patients who underwent ductoscopy at Beth Israel Medical Center from November 2001 to February 2004 was performed. The indications for ductoscopy were a persistent nipple discharge, high-risk status, or intraoperative margin assessment in patients undergoing lumpectomy. RESULTS: Seventy-four patients underwent ductoscopic evaluation of 88 ducts. Of the 32 patients who underwent office ductoscopy, 15 were high risk, and 17 had spontaneous nipple discharge. Spontaneous nipple discharge was the indication for ductoscopy in 40 of 42 intraoperative procedures. The remaining two patients underwent ductoscopy for margin assessment during breast conservation, and final pathologic analysis revealed negative margins. Thirty-eight of the 40 patients who had spontaneous nipple discharge had abnormal findings during ductoscopy and therefore underwent ductoscopically guided duct excision. Carcinoma was the final diagnosis in 5 (8.8%) of the 57 patients who were scoped for nipple discharge. CONCLUSIONS: Mammary ductoscopy is a potentially useful tool in the evaluation of patients with spontaneous nipple discharge. This is a well-tolerated office procedure with minimal risks and complications. Mammary ductoscopy may have a role in the assessment of high-risk women. Further research is necessary to confirm these potential applications.

Presurgical trial of metformin in overweight and obese patients with newly diagnosed breast cancer.

INTRODUCTION: We conducted a presurgical trial to assess the tissue-related effects of metformin in overweight/obese breast cancer (BC) patients. METHODS: Metformin 1,500 mg daily was administered to 35 nondiabetics with stage 0-III BC, body mass index (BMI) ≥ 25 kg/m(2). The primary endpoint was tumor proliferation change (i.e., ki-67). Tumor proliferation change was compared to untreated historical controls, matched by age, BMI, and stage. RESULTS: There was no reduction in ln(ki-67) after metformin (p = .98) or compared to controls (p = .47). There was a significant reduction in BMI, cholesterol, and leptin. CONCLUSION: Despite no proliferation changes, we observed reductions in other relevant biomarkers.

Risk-Stratified Intraoperative Radiation Therapy as a Definitive Adjuvant Radiation Therapy Modality for Women With Early Breast Cancer.

Radiation therapy is an integral component of adjuvant therapy in women who undergo breast conservative surgery, decreasing the likelihood of tumor recurrence and extending survival. The likelihood of tumor recurrence is highest within a proximity of the lumpectomy cavity, which prompted the idea of partial breast irradiation in place of the usual standard-of-care treatment with external beam whole breast radiation therapy. Targeted intraoperative radiation therapy (TARGIT-A) is a multicenter trial initially developed in 1999 and designed as a randomized clinical trial comparing whole breast radiation therapy to risk-adapted intraoperative radiation therapy (IORT). TARGIT-A recruited its first patient in March 2000, with the study concluding in 2012. At a median follow-up of 8.6 years, the prepathology TARGIT-A trial noted results to be noninferior to external beam radiation therapy, with no statistically significant difference in ipsilateral breast tumor recurrence, mastectomy-free survival, distant disease-free survival, or breast cancer-specific mortality. These results are consistent with the majority of retrospective and prospective trials. Risk-adapted IORT, as performed in the prospective randomized TARGIT-A trial, gives level 1 evidence that this approach is a standard option in the treatment of breast cancer.

Insulin resistance and racial disparities in breast cancer prognosis: a multi-center cohort study.

The survival for breast cancer (BC) is improving but remains lower in Black women than White women. A number of factors potentially drive the racial differences in BC outcomes. The aim of our study was to determine if insulin resistance (defined as homeostatic model assessment for insulin resistance (HOMA-IR)), mediated part of the relationship between race and BC prognosis (defined by the improved Nottingham prognostic index (iNPI)). We performed a cross-sectional study, recruiting self-identified Black and White women with newly diagnosed primary invasive BC from 10 US hospitals between March 2013 and February 2020. Survey, anthropometric, laboratory, and tumor pathology data were gathered, and we compared the results between Black and White women. We calculated HOMA-IR as well as iNPI scores and examined the associations between HOMA-IR and iNPI. After exclusions, the final cohort was 1206: 911 (76%) White and 295 (24%) Black women. Metabolic syndrome and insulin resistance were more common in Black than White women. Black women had less lobular BC, three times more triple-negative BC, and BCs with higher stage and iNPI scores than White women (P < 0.001 for all comparisons). Fewer Black women had BC genetic testing performed. HOMA-IR mediated part of the association between race and iNPI, particularly in BCs that carried a good prognosis and were hormone receptor (HR)-positive. Higher HOMA-IR scores were associated with progesterone receptor-negative BC in White women but not Black women. Overall, our results suggest that HOMA-IR contributes to the racial disparities in BC outcomes, particularly for women with HR-positive BCs.

The effect of modifiable risk factors on breast cancer aggressiveness among black and white women.

INTRODUCTION: Although breast cancer incidence is higher among white women, black women are more likely to have aggressive tumors with less favorable histology, and to have a worse prognosis. Obesity and alcohol consumption have been identified as two modifiable risk factors for breast cancer, while physical activity may offer protection. Little however is known about the association of these factors with race on the severity of breast cancer. METHODS: Data collected as part of a large prospective study looking at insulin resistance and race among women with breast cancer was queried for patient characteristics, lifestyle factors and tumor characteristics. The association with Nottingham Prognostic Index (NPI) was assessed with different models using univariate and multivariate linear regression. RESULTS: Among 746 women in our cohort, 82% (n = 615) were white and 18% (n = 131) were black, mean age 58 years. Black patients were more likely to have high BMI (31.0 vs. 26.7, p < 0.0001), comorbidities (69% vs 55%, p = 0.01), self-reported poor diet (70% vs 42%, p < 0.001), be sedentary (56% vs 46%, p = 0.03) and were less likely to consume alcohol (8% vs 32%, p < 0.0001) compared to white patients. Overall, 137 (18%) of the patients had poorer prognosis (NPI > 4.4), which was significantly associated with younger age (55.6 vs 58.5 years, p = 0.02), black race (27% vs 15%, p = 0.001), triple negative cancer (15% vs 6%, p = 0.003), and poor diet (54% vs 45%, p = 0.046) compared to patients with better prognosis (NPI ≤ 4.4). On multivariate analysis, (model R2 = 0.12; p < 0.001), age (ß = -0.011 per year, p = 0.002), healthy diet (ß = -0.195, p = 0.02), and exercise (ß = -0.004, p = 0.02) were associated with better prognosis, while black race (ß = 0.247, p = 0.02) and triple negative cancer (ß = 0.908, p < 0.0001) were associated with poor prognosis. Neither alcohol use nor BMI was significantly associated with NPI. CONCLUSION: Among modifiable risk factors, diet and exercise are associated with NPI. Unmodifiable factors including race and biologic subtype remain the most important determinants of prognosis.

A skin dose prediction model based on in vivo dosimetry and ultrasound skin bridge measurements during intraoperative breast radiation therapy.

PURPOSE: Using in vivo measurements from optically stimulated luminescence dosimeters (OSLDs) to develop and validate a prediction model for estimating the skin dose received by patients undergoing breast intraoperative radiation therapy (IORT). METHODS AND MATERIALS: IORT was performed using INTRABEAM-600 with spherical applicators placed in the lumpectomy cavity. Ultrasound skin bridge measurements were used to determine the applicator-to-skin distance, with OSLDs placed to measure the skin surface dose at the corresponding points. The OSLD response was calibrated for the 50 kVp INTRABEAM-600 output. Models were fit to describe the dose fall-off with increasing applicator-to-skin distance and the best fitting model was chosen for estimating skin dose. RESULTS: Twenty four patients with 25 lumpectomy cavities were included, and the average skin dose recorded was 1.18 Gy ± 0.88 Gy, ranging from 0.17 Gy to 4.77 Gy, with an average applicator-to-skin distance of 19.9 mm ± 5.1 mm. An exponential-plateau model was found to best describe the dose fall-off with a root-mean-square error of 0.73. This model was then validated prospectively using skin dose measurements from five consecutive patients. Validation measurements were well within the 95% prediction limits of the model, with a root-mean-square error of 0.52, showing that the prediction model accurately estimates skin dose using ultrasound skin bridge measurements. CONCLUSIONS: This prediction model constitutes a useful tool for estimating the skin dose received during breast lumpectomy IORT. The model and accompanying 95% confidence intervals can be used to establish a minimum allowable skin bridge distance, effectively limiting the maximum allowable skin dose.

The role of mammary ductoscopy in breast cancer: a review of the literature.

Breast cancer is the most frequently diagnosed malignancy among American women. It is the second most common cause of cancer death. Genetic analysis using comparative genetic hybridization (CGH) has shown evidence that the majority of breast cancers, approximately 85%, begin in the ductal epithelium with normal cells progressing to atypia and finally to carcinoma. Mammary ductoscopy, also referred to as the intraductal approach, is a new tool that allows direct visualization of the breast ductal system. It enables one to sample the ductal epithelium and may allow identification of early changes cytologically as well as potentially play an important role in aiding surgical excision. This may aid in detection of breast masses long before they are palpable or visible via mammography. Mammary ductoscopy may have a role in the evaluation of women with nipple discharge, high-risk women, or limiting the amount of tissue removed in breast conservation surgery for cancer.

Mammary ductoscopy for evaluation of nipple discharge.

BACKGROUND: Most breast cancers originate in the ductal epithelium with normal cells progressing to atypia and finally to carcinoma. Ductoscopy enables one to visualize and sample the ductal epithelium and therefore identify early changes cytologically. This report describes our experience with mammary ductoscopy as a tool for evaluation of nipple discharge at Beth Israel Medical Center. METHODS: A prospective review of all patients who have undergone ductoscopy for evaluation of persistent nipple discharge was performed. The Acueity ductoscopy system with .9-mm scope and a video monitor with x60 magnification were used. Brush biopsy samples and lavage fluid were obtained from some patients and were sent for cytologic analysis. A subset of patients underwent ductoscopically guided duct excision. RESULTS: Ninety-three patients underwent ductoscopic evaluation of 110 ducts. Of these, 67 patients had abnormal findings and therefore underwent ductoscopically guided duct excision. The remaining 26 patients (28%) had normal ductoscopic examinations. The depth at which intraductal abnormalities were visualized was from 3 to 8 cm with an average of 4.4 cm for cancer cases and from 1 to 10 cm with an average of 4.5 cm for papillomas. Forty-two patients were diagnosed with papilloma/papillomatosis, six patients were diagnosed with atypical papilloma/atypical ductal hyperplasia/atypical lobular hyperplasia, and six patients were diagnosed with cancer. Of the six patients diagnosed with cancer, 67% had normal breast imaging, and other than nipple discharge, 67% had normal breast examinations. CONCLUSION: Mammary ductoscopy is a useful tool in the evaluation of patients with nipple discharge. Although the most common cause of nipple discharge is an intraductal papilloma, nipple discharge can be the presenting symptom for cancer. Our experience revealed a papilloma rate of 45% (42 of 93), cancer rate of 6.5% (6 of 93), and an atypia rate of 6.5% (6 of 93) among the patients with nipple discharge. Mammary ductoscopy allows for accurate visualization, analysis, and excision of intraductal abnormalities. Many deeper intraductal abnormalities could be missed by blind surgical excision.

Paraneoplastic cerebellar degeneration with anti-Yo antibody in a patient with HER2/neu overexpressing breast cancer: a case report with a current literature review.

Paraneoplastic cerebellar degeneration (PCD) is a rare paraneoplastic syndrome, occurring in <1% of breast cancers. We describe a 32-year-old female presenting with ataxia subsequently diagnosed with poorly differentiated breast cancer. She was serum anti-Yo antibody positive, with estrogen/progesterone receptor negative and HER2/neu receptor positive breast cancer. Neurological symptoms progressed despite modified radical mastectomy, supraclavicular lymphadenectomy, intravenous immunoglobulin, corticosteroids, transtuzumab, and combination chemotherapy. We performed a literature search, which found a possible association between anti-Yo positive PCD and HER2/neu-expressing breast cancer.