Society of Surgical Oncology Breast Disease Site Working Group Statement on Contralateral Mastectomy: Indications, Outcomes, and Risks.

Rates of contralateral mastectomy (CM) among patients with unilateral breast cancer have been increasing in the United States. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, risks, and benefits of CM since the society's 2017 statement. We held a virtual meeting to outline key topics and then conducted a literature search using PubMed to identify relevant articles. We reviewed the articles and made recommendations based on group consensus. Patients consider CM for many reasons, including concerns regarding the risk of contralateral breast cancer (CBC), desire for improved cosmesis and symmetry, and preferences to avoid ongoing screening, whereas surgeons primarily consider CBC risk when making a recommendation for CM. For patients with a high risk of CBC, CM reduces the risk of new breast cancer, however it is not known to convey an overall survival benefit. Studies evaluating patient satisfaction with CM and reconstruction have yielded mixed results. Imaging with mammography within 12 months before CM is recommended, but routine preoperative breast magnetic resonance imaging is not; there is also no evidence to support routine postmastectomy imaging surveillance. Because the likelihood of identifying an occult malignancy during CM is low, routine sentinel lymph node surgery is not recommended. Data on the rates of postoperative complications are conflicting, and such complications may not be directly related to CM. Adjuvant therapy delays due to complications have not been reported. Surgeons can reduce CM rates by encouraging shared decision making and informed discussions incorporating patient preferences.

Are There Disparities in Breast Reconstruction After Contralateral Prophylactic Mastectomy?

INTRODUCTION: Despite national guidelines against contralateral prophylactic mastectomy (CPM) in low- to moderate-risk breast cancer, CPM use continues to rise. Breast reconstruction improves health-related quality of life and satisfaction among women undergoing mastectomy. Given the lack of data regarding factors associated with reconstruction after CPM and the known benefits of reconstruction, we sought to investigate whether disparities exist in receipt of reconstruction after CPM. METHODS: The 2004-2017 National Cancer Database was queried to identify women diagnosed with breast cancer who underwent unilateral mastectomy with CPM. Patients were divided into two groups: those who underwent planned reconstruction at any timepoint and those who did not. A secondary analysis comparing types of reconstruction (tissue, implant, combined) was conducted. Patient, tumor, and demographic characteristics were analyzed using chi-square test and odds ratios were calculated using generalized estimating equations. RESULTS: The cohort included 1,73,249 women: 95,818 (55.3%) underwent reconstruction and 77,431 (45.7%) did not. Both the rate CPM and the proportion of women undergoing reconstruction after CPM increased between 2004 and 2017. Of the women who had reconstruction, 40,840 (51.7%) received implants, 29,807 (37.7%) had tissue, and 8352 (10.6%) had combined reconstruction. After adjusted analysis, factors associated with reconstruction were young age, Hispanic ethnicity, private insurance, and living in an area with the highest education and median income (P < 0.01). Patients who underwent reconstruction were less likely to have radiation (P < 0.01) and chemotherapy (P < 0.01), more likely to have stage I disease (P < 0.01), and to be treated at an integrated cancer center (P < 0.01). CONCLUSIONS: Reconstruction after CPM is disproportionately received by younger women, Hispanics, those with private insurance, and higher socioeconomic status and education. While the rate of reconstruction after CPM is increasing, there remain significant disparities. Conscious efforts must be made to eliminate these disparities, especially given the known benefits of reconstruction after mastectomy.

The POWER-PAK Score Characterizes Tumor Response to 3 Months of Preoperative Endocrine Therapy.

BACKGROUND: The Pre-Operative Window of Endocrine Therapy to Inform Radiation Therapy Decisions (POWER, NCT04272801) trial aims to determine whether 3 months of preoperative endocrine therapy (pre-ET) informs adjuvant radiation therapy decisions among older women with early stage, ER-positive breast cancer. We propose the POWER Pathologic Assessment and Ki-67 (POWER-PAK) scoring system to characterize the histologic effects of pre-ET. METHODS: Histologic evaluation was performed on core biopsy and lumpectomy specimens from 37 POWER trial participants who completed pre-ET and surgery. The POWER-PAK score consists of tumor regression, decrease in Ki-67 expression, and ER expression, each ranging from 0 to 2. Scores were aggregated to create the POWER-PAK score with a range from 0 to 6. Participants with no residual tumor were labelled 6-NRT. RESULTS: ER expression did not decrease after pre-ET. Ki-67 decreased from 13% in biopsy specimens to 5% in the lumpectomy specimens (p < 0.001). Cellularity decreased from 40% to 23% (p < 0.001). There was heterogeneity of POWER-PAK scores ranging from 2 to 6-NRT: score of 2, n = 2 (5.4%); 4, n = 8 (21.6%); 5, n = 4 (10.8%); 6, n = 16 (43.2%); and 6-NRT, n = 7 (18.9%). Participants with a score ≥ 5 were more likely to have smaller tumors after pre-ET compared with those with a score < 5 (p = 0.04). CONCLUSIONS: The tumor responses following treatment with pre-ET are heterogenous. We propose that the POWER-PAK scoring system can be used to quantify response to pre-ET. Future studies will explore the use of POWER-PAK to support informed decision-making for adjuvant therapy options for older women with early stage breast cancer.

Factors Associated With Cosmetic Outcomes After Treatment With a Novel Form of Breast Intraoperative Radiation Therapy.

INTRODUCTION: Precision breast intraoperative radiation therapy (PB-IORT) incorporates computed tomography-guided treatment planning and high dose rate brachytherapy to deliver a single dose of highly conformal radiational therapy. The purpose of this study is to determine factors associated with poor cosmetic outcomes after treatment with PB-IORT. METHODS: The study included all consecutive participants enrolled in an ongoing phase II clinical trial that had completed a minimum of 12 mo of follow-up. A poor cosmetic outcome was defined as scoring "fair" or "poor" on the Harvard Cosmesis evaluation, or "some" or "very much" on any of the three general cosmesis categories. Statistical analysis was performed utilizing R. RESULTS: The final cohort included 201 participants, of which 181 (90%) had an overall good/excellent cosmetic outcome. Group 1 consisted of 162 (81%) participants who reported only excellent/good cosmetic outcomes. Group 2 consisted of 39 (19%) participants who reported some aspect of a poor cosmetic outcome. On multivariable analysis, participants with ductal carcinoma in situ were significantly more likely to experience a poor cosmetic outcome (odds ratio 2.45, 95% confidence interval 1.03-5.82, P = 0.04), and those who received subsequent whole breast irradiation were also more likely to have a poor cosmetic outcome (odds ratio 10.20, 95% confidence interval CI 1.04-99.95, P = 0.04). CONCLUSIONS: Patients with need for further radiation after PB-IORT are at increased risk for a poor cosmetic outcome. Larger balloon volume and distance between the skin do not have deleterious effects on cosmetic outcomes.

Cancer Screening and Treatment Delays During the COVID-19 Pandemic and the Role of Health Literacy in Care Re-engagement: Findings from an NCI-Designated Comprehensive Cancer Center sample.

The COVID-19 pandemic has led to numerous delays in cancer-related care and cancer-specific screening, but the extent is not fully understood. For those that experience a delay or disruption in care, health related self-management is required to re-engage in care pathways and the role of health literacy in this pathway has not been explored. The purpose of this analysis is to (1) report the frequency of self-reported delays in cancer treatment and preventative screening services at an academic, NCI-designated center during the COVID-19 pandemic and (2) investigate cancer-related care and screening delays among those with adequate and limited health literacy. A cross-sectional survey was administered from an NCI-designated Cancer Center with a rural catchment area during November 2020 through March 2021. A total of 1,533 participants completed the survey, and nearly 19 percent of participants were categorized as having limited health literacy. Twenty percent of those with a cancer diagnosis reported a delay in cancer-related care; and 23-30% of the sample reported a delay in cancer screening. In general, the proportions of delays among those with adequate and limited health literacy were similar with the exception of colorectal cancer screening. There was also a notable difference in the ability to re-engage in cervical cancer screening among those with adequate and limited health literacy. Thus, there is a role for those engaged in cancer-related education and outreach to offer additional navigation resources for those at risk to cancer-related care and screening disruptions. Future study is warranted to investigate the role of health literacy on cancer care engagement.

Impact of the COVID-19 pandemic on breast cancer screening volumes and patient screening behaviors.

PURPOSE: In order to facilitate targeted outreach, we sought to identify patient populations with a lower likelihood of returning for breast cancer screening after COVID-19-related imaging center closures. METHODS: Weekly total screening mammograms performed throughout 2019 (baseline year) and 2020 (COVID-19-impacted year) were compared. Demographic and clinical characteristics, including age, race, ethnicity, breast density, breast cancer history, insurance status, imaging facility type used, and need for interpreter, were compared between patients imaged from March 16 to October 31 in 2019 (baseline cohort) and 2020 (COVID-19-impacted cohort). Census data and an online map service were used to impute socioeconomic variables and calculate travel times for each patient. Logistic regression was used to identify patient characteristics associated with a lower likelihood of returning for screening after COVID-19-related closures. RESULTS: The year-over-year cumulative difference in screening mammogram volumes peaked in week 21, with 2962 fewer exams in the COVID-19-impacted year. By week 47, this deficit had reduced by 49.4% to 1498. A lower likelihood of returning for screening after COVID-19-related closures was independently associated with younger age (odds ratio (OR) 0.78, p < 0.001), residence in a higher poverty area (OR 0.991, p = 0.014), lack of health insurance (OR 0.65, p = 0.007), need for an interpreter (OR 0.68, p = 0.029), longer travel time (OR 0.998, p < 0.001), and utilization of mobile mammography services (OR 0.27, p < 0.001). CONCLUSION: Several patient factors are associated with a lower likelihood of returning for screening mammography after COVID-19-related closures. Knowledge of these factors can guide targeted outreach to vulnerable patients to facilitate breast cancer screening.

Effects of Adjuvant Endocrine Therapy Adherence and Radiation on Recurrence and Survival Among Older Women with Early-Stage Breast Cancer.

BACKGROUND: The Cancer and Leukemia Group-B 9343 (CALGB 9343) trial demonstrated that women aged ≥ 70 years with early-stage breast cancer can safely omit radiation therapy (RT) and be treated with breast-conserving surgery (BCS) and adjuvant endocrine therapy (AET) alone. AET adherence is low, leaving an undertreated cohort who may be at increased risk of recurrence and death. We hypothesized that AET adherence and adjuvant treatment choice impact recurrence and survival among CALGB 9343 eligible women. PATIENTS AND METHODS: SEER-Medicare was used to identify CALGB 9343 eligible women who underwent BCS between 2007 and 2016. Medicare claims were used to identify AET use, and the proportion of days covered by AET was used to categorize adherent (PDC ≥ 0.80) versus nonadherent patients (PDC < 0.80). Recurrence-free, cancer-specific, and overall survival were assessed using Cox proportional hazards models. RESULTS: In total, 10,719 women were identified, of whom 780 (7.3%) underwent BCS alone, 1490 (13.9%) underwent BCS + RT, 1663 (15.5%) underwent BCS + AET, and 6786 (63.3%) had BCS + RT + AET. Among women treated with BCS + AET, adherent patients had lower recurrence than did nonadherent patients (HR = 0.65, 95% CI: 0.50-0.85). With respect to adjuvant treatment combinations, there was no recurrence difference between the BCS + RT + AET group and BCS + AET group (HR = 0.81, 95% CI: 0.54-1.21). There was equivalent cancer-specific but worse overall survival in the BCS + AET group versus the BCS + AET + RT group. CONCLUSIONS: While BCS + RT + AET may represent overtreatment for some, AET nonadherent women who omit RT are at risk for worse outcomes. Treatment decisions regarding RT omission should be tailored to the individual patient, taking into consideration the chances of AET nonadherence and the patients' own risk tolerance.

Childhood cancer survivors face markedly worse overall survival after diagnosis with breast cancer, melanoma, or colorectal cancer.

BACKGROUND: Childhood cancer survivors (CCS) are at elevated risk of secondary malignancies (SM). Enhanced screening for SM is recommended, but compliance is poor. We hypothesized that CCS with adult-onset SM (colorectal cancer [CRC], melanoma, or breast cancer [BC]) would present with more advanced disease and have decreased overall survival (OS). METHODS: The Surveillance, Epidemiology, and End Results Program was queried for patients diagnosed with cancer at age less than or equal to 18 also diagnosed with adult-onset CRC, melanoma, or BC. A cohort without a history of prior malignancy was likewise identified. Tumor features and clinical outcomes were compared. RESULTS: CCS with a SM (n = 224) were compared with patients without a childhood cancer history (n = 1,392,670). CCS were diagnosed younger (BC = 37.6 vs. 61.3, p < 0.01, CRC = 35.0 vs. 67.1, p < 0.01, melanoma = 29.6 vs. 61.3 years old, p < 0.01). CCS with BC were more likely to have Stage III or IV disease (25.2% vs. 16.5%, p = 0.01). Hormone-receptor expression also differed; CCS were less likely to develop Luminal A-type tumors (48.6% vs. 66.9%, p = 0.01). After age-adjustment, CCS had worse OS (Hazard ratio: CRC = 2.449, p < 0.01, melanoma = 6.503, p < 0.01, BC = 3.383, p < 0.01). CONCLUSION: CCS were younger when diagnosed with a SM. After age-adjustment, OS was diminished. Heightened surveillance may be necessary for CCS diagnosed with SM.

Predicting adjuvant endocrine therapy initiation and adherence among older women with early-stage breast cancer.

PURPOSE: The CALGB 9343 trial demonstrated that women age 70 or older with early-stage, estrogen receptor positive (ER +) breast cancer (BC) may safely forgo radiation therapy (RT) and be treated with breast conserving surgery followed by adjuvant endocrine therapy (AET) alone. However, most patients in this population still undergo RT in part because AET adherence is low. We sought to develop a predictive model for AET initiation and adherence in order to improve decision-making with respect to RT omission. METHODS: Women ages 70 and older with early-stage, ER + BC were identified using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Comorbidities, socioeconomic measures, prescription medications, and demographics were collected as potential predictors. Bivariate analysis was performed to identify factors associated with AET initiation and adherence. Stepwise selection of significant predictors was used to develop logistic regression classifiers for initiation and adherence. Model performance was evaluated using the c-statistic and other measures. RESULTS: 11,037 patients met inclusion criteria. Within the cohort, 8703 (78.9%) patients initiated AET and 6685 (60.6%) were adherent to AET over 1 year. Bivariate predictors of AET initiation were similar to predictors of adherence. The best AET initiation and adherence classifiers were poorly predictive with c-statistics of 0.65 and 0.60, respectively. CONCLUSIONS: The best models in the present study were poorly predictive, demonstrating that the reasons for initiation and adherence to AET are complex and individual to the patient, and therefore difficult to predict. Initiation and adherence to AET are important factors in decision-making regarding whether or not to forgo adjuvant RT. In order to better formulate treatment plans for this population, future work should focus on improving individual prediction of AET initiation and adherence.

Evaluating the Long-Term Impact of a Cooperative Group Trial on Radiation Use and Adjuvant Endocrine Therapy Adherence Among Older Women.

BACKGROUND: Using long-term survival data from the C9343 trial as a temporal reference point, this study aimed to determine radiation therapy (RT) treatment trends for older patients with early-stage breast cancer. The study also examined rates of adherence to adjuvant endocrine therapy (AET). METHODS: The surveillance, epidemiology, and end results-medicare database was used to identify women with a diagnosis of breast cancer from 2007 through 2016. Bivariate associations were calculated to determine variable characteristics by time frame (group 1: 2007-2012 vs. group 2: 2013-2016). Multivariate logistic regression was used to estimate the effect of group on the RT use and AET adherence. The temporal rates for both RT and AET adherence over time were plotted. RESULTS: The final study cohort included 12,210 Medicare beneficiaries. Use of RT differed significantly between the groups, with a higher proportion omitting RT in the later period (25% of group 2 vs. 20% of group 1; p < 0.001). In both groups, after adjustment for covariates, the patients with RT omitted were statistically less likely to adhere to AET [group 1: odds ratio (OR), 0.74; p < 0.001 vs. group 2: OR, 0.66; p < 0.001]. CONCLUSION: This study, 15 years after publication of the of the C9343 trial results, showed minimal change in practice, with most older women receiving RT. Importantly, AET adherence was significantly lower in the non-RT group. For women who meet the criteria to have adjuvant RT omitted, nonadherence to AET could result in undertreatment of their breast cancer, and RT should not be considered overtreatment.

Long-term Impact of CALGB 9343 on Radiation Utilization.

BACKGROUND: The results of the Cancer and Leukemia Group B (CALGB) 9343 trial showed that radiation therapy (RT) did not improve survival for women older than 70 y with early-stage estrogen receptor + breast cancer treated with breast conserving surgery and adjuvant endocrine therapy. In 2005, guidelines were modified to allow for RT omission; however, minimal change in clinical practice has occurred. The aim of this study was to determine if CALGB long-term follow-up data have affected RT utilization, and to characterize the population still receiving RT after breast conserving surgery. METHODS: The Surveillance, Epidemiology, and End Results-Medicare database was used to identify women diagnosed with early-stage breast cancer from 2004 to 2015 who matched the CALGB 9343 inclusion criteria. Multivariate logistic regression was carried out to identify the factors that affect the receipt of radiation therapy. We also plotted the overall use of RT over time juxtaposed with the temporal trends of CALGB 9343 clinical trial data, guideline recommendations, and publishing of long-term survival data. RESULTS: The study cohort included 25,723 Medicare beneficiaries, of whom 20,328 (79%) received RT and 5395 (21%) did not receive RT. In a multivariate model, the frequency of RT omission increased over time, with those diagnosed in year 2015 being 2.72 times more likely to omit RT compared with those diagnosed in 2004 (95% confidence interval 2.31-3.19). CONCLUSIONS: This study investigated the impact of long-term CALGB 9343 data on clinical practice. The results of this study support results from previous studies, extend the dates of analysis, and indicate that after long-term follow-up of CALGB 9343 data, RT was less used, but overall trends did not dramatically decrease.

Diabetes Mellitus and Metformin Are Not Associated With Breast Cancer Pathologic Complete Response.

BACKGROUND: Metformin use has been linked to pathologic complete response (pCR) following neoadjuvant chemotherapy for several malignancies. We aimed to investigate the association of diabetes mellitus (DM) and metformin use with pCR in breast cancer. MATERIALS AND METHODS: All breast cancer patients who received neoadjuvant chemotherapy during June 2013-October 2016 at two academic medical centers were identified. A retrospective cohort study evaluated patients who did and did not achieve pCR. Multivariable logistic regression identified independent predictors of pCR, specifically looking at metformin use and DM. RESULTS: The study group included 351 breast cancer patients, with 90 (25.6%) achieving pCR after neoadjuvant chemotherapy. The rate of DM did not differ between those with and without pCR, nor did the rate of metformin use. Multivariable logistic regression identified HER2-positive tumors and smaller preoperative tumor size as predictors of pCR. The estrogen receptor (ER) positivity was associated with an absence of pCR. Importantly, neither DM nor metformin use was predictive of pCR. CONCLUSIONS: This study by the two institutions supports previous data of tumor-related factors known to be associated with pCR; however, the current analysis found neither DM nor metformin to be independently associated with pCR. Thus, additional prospective study is warranted prior to validating metformin as an antitumor agent.

Normal tissue dose and risk estimates from whole and partial breast radiation techniques.

PURPOSE: To compare radiation dose to organs at risk in patients with early-stage breast cancer treated with lumpectomy and intraoperative radiation therapy with CT-guided HDR brachytherapy (precision breast IORT; PB-IORT) and those treated with external beam whole breast irradiation (WB-DIBH) or partial breast irradiation (PB-DIBH) with deep inspiratory breath hold. METHODS: We retrospectively identified 52 consecutive patients with left-sided breast cancers treated with either PB-IORT (n = 17, 76% outer breast) on a phase I clinical trial, adjuvant PB-DIBH (n = 18, 56% outer breast, 6% cavity boost), or WB-DIBH (n = 17, 76% outer breast, 53% with lumpectomy cavity boost). Conventional (2 Gy/fraction) or moderate hypofractionation (2.66 Gy/fraction) was prescribed for the external beam cohorts and 12.5 Gy in 1 fraction to 1 cm from the balloon surface was prescribed to the HDR brachytherapy cohort. CT-based planning was used for all patients. Organ at risk doses and excess risk ratios (ERR) for secondary lung cancers, contralateral breast cancers, and cardiac toxicity were compared between treatment techniques. RESULTS: Compared to WB-DIBH and PB-DIBH, PB-IORT resulted in lower ipsilateral lung V5, V10, V20, mean, and max dose (P < .05). Mean ipsilateral lung BED3Gy was as follows: 1.32 Gy for PB-IORT, 4.33 Gy for WB-DIBH, 3.35 Gy for PB-DIBH. The ERR for lung cancer was lowest for PB-IORT (P < .001). There was significantly higher contralateral breast max dose but lower mean BED3Gy for WB-DIBH compared with PB-IORT (P = .012, P = .011, respectively). Mean contralateral breast BED3Gy was as follows: 0.10 Gy for PB-IORT, 0.06 Gy for WB-DIBH, and 0.08 Gy for PB-DIBH. The ERR for contralateral breast cancer was low for all breast techniques, but WB-DIBH showed lower ERR compared to PB-IORT (P = .019). Mean heart BED2Gy was higher with PB-IORT at 1.26 Gy compared to 0.48 Gy and 0.24 Gy for WB-DIBH and PB-DIBH, respectively (P < .001). CONCLUSIONS: Patients with early-stage breast cancer treated with PB-IORT and with tissue-sparing external beam techniques all received low organ at risk doses, but PB-IORT resulted in far lower ipsilateral lung dose compared with external beam techniques. Our data indicate the lowest mean contralateral breast BED in the WB-DIBH group, likely due to the simplicity of the field design in low-risk patients using tangential whole breast radiation. External beam using DIBH results in lowest heart dose, but all techniques were well within recommended heart constraints.

The impact of bariatric surgery on qualitative and quantitative breast density.

BACKGROUND: Obesity and breast density are associated with breast cancer in postmenopausal women. Bariatric surgery effectively treats morbid obesity, with sustainable weight loss and reductions in cancer incidence. We evaluated changes in qualitative and quantitative density; hypothesizing breast density would increase following bariatric surgery. METHODS: Women undergoing bariatric surgery from 1990 to 2015 were identified, excluding patients without a mammogram performed both before and after surgery. Changes in body mass index (BMI), time between mammograms and surgery, and American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) scores were assessed. VolparaDensity™ automated software calculated volumetric breast density (VBD), fibroglandular volume (FGV), and total breast volume for the 82 women with digital data available. Differences between pre- and postsurgery values were assessed. RESULTS: One hundred eighty women were included. Median age at surgery was 50.0 years, with 8.8 months between presurgery mammogram and surgery and 62.3 months between surgery and postsurgery mammogram. Median BMI significantly decreased over the study period (46.0 vs 35.4 kg/m2 ; P < 0.001). No change in BI-RADS scores was seen between the pre- and postsurgery mammograms. Eighty-two women had VolparaDensity™ data available. While VBD increased in these patients, FGV and total breast volume both decreased following bariatric surgery. CONCLUSIONS: Increased VBD, decreased FGV, and decreased total breast volume were seen following bariatric surgery-induced weight loss. There was no difference in qualitative breast density, highlighting the discrepancy between BI-RADS and VolparaDensity™ measurements. Further investigation will be required to determine how differential changes in components of breast density may affect breast cancer risk.

Impact of patient health literacy on surgical treatment of breast cancer.

Little is known about the role of low health literacy (LHL) among breast surgical oncology patients. We initiated a prospective health literacy assessment to determine the relationship between health literacy and surgical treatment. Among 512 patients, univariate analysis revealed no statistical significance in the relationship of health literacy to breast surgery type, contralateral prophylactic mastectomy, or reconstruction following mastectomy. In a multivariate analysis, women with LHL were less likely to undergo reconstruction (aOR 0.81, 95% CI 0.69-0.94, P value = .006). Tailored interventions are needed to combat disparities in cancer treatment associated with LHL, with focus on reconstruction following mastectomy.

Survival after Breast-Conserving Surgery with Whole Breast or Partial Breast Irradiation in Women with Early Stage Breast Cancer: A SEER Data-base Analysis.

Randomized clinical trials have demonstrated equivalency in survival outcomes for early stage breast cancer patients treated with either mastectomy or breast-conserving surgery (BCS) with radiation. Recent, state-level data confirm comparable survival outcomes. Using Surveillance Epidemiology and End Research (SEER) data, we sought to evaluate survival outcomes among patients with early stage breast cancer treated with mastectomy, BCS with whole breast irradiation (BCS + WBI), or BCS with accelerated partial breast irradiation (BCS + APBI). Data on women 50 years or older diagnosed with a node negative invasive breast cancer (≤3 cm in size) between 1995 and 2009 were extracted from the SEER data base. Women treated with mastectomy alone or BCS with radiation were eligible for analysis. Kaplan-Meier estimates and Cox proportional hazard models were used to compare overall survival (OS) and cancer-specific survival (CSS) among the treatment groups. 150,171 women fulfilled inclusion criteria. OS was significantly improved among women treated with BCS and WBI or BCS and APBI compared to mastectomy alone. Adjusted hazard ratios for death in BCS with WBI or APBI (versus mastectomy alone) were 0.73 (95% CI: 0.71, 0.76) and 0.68 (95% CI: 0.58, 0.79), respectively. Adjusted CSS was also significantly improved in patients treated with BCS and WBI (HR 0.80, 95% CI: 0.76, 0.85) as compared to mastectomy. BCS with radiation (WBI or APBI) was associated with significantly improved OS and CSS, versus mastectomy alone. These results support the use of BCS with WBI or APBI (in well selected patients) for the treatment of breast cancer.

Techniques for intraoperative radiation therapy for early-stage breast carcinoma.

Intraoperative radiation therapy (IORT) is a method of accelerated partial breast irradiation developed to replace other longer courses of radiotherapy with a single radiation session administered at the time of breast-conserving surgery. The purpose of this review is to summarize the advantages and disadvantages of breast IORT techniques that are currently available, as well to consider potential alternative techniques for breast IORT or ultra-short course breast radiotherapy. Furthermore, we highlight the published outcomes for the IORT treatment approaches including: electron therapy, superficial photon therapy and other techniques. Potential future directions of IORT are explored including novel IORT techniques utilizing intraoperative brachytherapy with in-room imaging and rapid treatment planning.

Patient-derived response estimates from zero-passage organoids of luminal breast cancer.

Background: Primary luminal breast cancer cells lose their identity rapidly in standard tissue culture, which is problematic for testing hormone interventions and molecular pathways specific to the luminal subtype. Breast cancer organoids are thought to retain tumor characteristics better, but long-term viability of luminal-subtype cases is a persistent challenge. Our goal was to adapt short-term organoids of luminal breast cancer for parallel testing of genetic and pharmacologic perturbations. Methods: We freshly isolated patient-derived cells from luminal tumor scrapes, miniaturized the organoid format into 5 µl replicates for increased throughput, and set an endpoint of 14 days to minimize drift. Therapeutic hormone targeting was mimicked in these "zero-passage" organoids by withdrawing ß-estradiol and adding 4-hydroxytamoxifen. We also examined sulforaphane as an electrophilic stress and commercial neutraceutical with reported anti-cancer properties. Downstream mechanisms were tested genetically by lentiviral transduction of two complementary sgRNAs and Cas9 stabilization for the first week of organoid culture. Transcriptional changes were measured by RT-qPCR or RNA sequencing, and organoid phenotypes were quantified by serial brightfield imaging, digital image segmentation, and regression modeling of cellular doubling times. Results: We achieved >50% success in initiating luminal breast cancer organoids from tumor scrapes and maintaining them to the 14-day zero-passage endpoint. Success was mostly independent of clinical parameters, supporting general applicability of the approach. Abundance of ESR1 and PGR in zero-passage organoids consistently remained within the range of patient variability at the endpoint. However, responsiveness to hormone withdrawal and blockade was highly variable among luminal breast cancer cases tested. Combining sulforaphane with knockout of NQO1 (a phase II antioxidant response gene and downstream effector of sulforaphane) also yielded a breadth of organoid growth phenotypes, including growth inhibition with sulforaphane, growth promotion with NQO1 knockout, and growth antagonism when combined. Conclusions: Zero-passage organoids are a rapid and scalable way to interrogate properties of luminal breast cancer cells from patient-derived material. This includes testing drug mechanisms of action in different clinical cohorts. A future goal is to relate inter-patient variability of zero-passage organoids to long-term outcomes.

Novel Form of Breast Intraoperative Radiation Therapy with CT-Guided High-Dose-Rate Brachytherapy: Interim Results of a Prospective Phase-II Clinical Trial.

BACKGROUND: Precision breast intraoperative radiation therapy (PB-IORT) is a novel method of IORT that uses customized CT-based treatment plans and high-dose-rate (HDR) brachytherapy. We conducted a phase-II multi-institution trial to evaluate the efficacy of PB-IORT. STUDY DESIGN: Between 2015 and 2022, 3 centers enrolled women aged 45 years and older with invasive or in situ carcinoma measuring 3 cm or smaller and N0 status (n = 358). Breast-conserving surgery was performed, and a multilumen balloon catheter was placed in the lumpectomy bed. CT images were used to create customized HDR brachytherapy plans that delivered 12.5 Gy to the tumor bed. The primary outcome assessed was the 5-year rate of index quadrant tumor recurrence. An interim analysis was conducted after one-third of eligible participants completed 5 years of follow-up. This trial is registered with clinicaltrials.gov (NCT02400658). RESULTS: The cohort comprised 153 participants with a median age of 64 years and median follow-up time of 5.9 years. The estimated 5-year index quadrant tumor recurrence rate and overall survival were 5.08% (95% CI 2.23 to 9.68) and 95.1%, respectively. Locoregional (ipsilateral breast and axilla) and distant recurrence rates were each 1.96%. Seven deaths occurred during the first 5 years of follow-up, with only 1 attributable to breast cancer. Overall, 68.6% of patients experienced any adverse effects, and 4 cases of breast-related severe toxicities were observed. CONCLUSIONS: This study presents the results of a planned interim analysis of a phase-II trial investigating PB-IORT and demonstrates the efficacy and safety of single-fraction, CT-based, HDR brachytherapy after breast-conserving surgery. These findings provide valuable insights into the use of PB-IORT as a treatment modality.