Internal Mammary Lymphadenopathy Does Not Impact Oncologic Outcomes in Patients Treated with Neoadjuvant Chemotherapy: Results from the I-SPY2 Clinical Trial.

BACKGROUND: Internal mammary lymphadenopathy (IML) plays a role in breast cancer stage and prognosis. We aimed to evaluate method of IML detection, how IML impacts response to neoadjuvant chemotherapy (NAC), and oncologic outcomes. METHODS: We evaluated patients enrolled in the I-SPY-2 clinical trial from 2010 to 2022. We captured the radiographic method of IML detection (magnetic resonance imaging [MRI], positron emission tomography/computed tomography [PET/CT], or both) and compared patients with IML with those without. Rates of locoregional recurrence (LRR), distant recurrence (DR) and event-free survival (EFS) were compared by bivariate analysis. RESULTS: Of 2095 patients, 198 (9.5%) had IML reported on pretreatment imaging. The method of IML detection was 154 (77.8%) MRI only, 11 (5.6%) PET/CT only, and 33 (16.7%) both. Factors associated with IML were younger age (p = 0.001), larger tumors (p < 0.001), and higher tumor grade (p = 0.027). Pathologic complete response (pCR) was slightly higher in the IML group (41.4% vs. 34.0%; p = 0.03). There was no difference in breast or axillary surgery (p = 0.41 and p = 0.16), however IML patients were more likely to undergo radiation (68.2% vs. 54.1%; p < 0.001). With a median follow up of 3.72 years (range 0.4-10.2), there was no difference between IM+ versus IM- in LRR (5.6% vs. 3.8%; p = 0.25), DR (9.1% vs. 7.9%; p = 0.58), or EFS (61.6% vs. 57.2%; p = 0.48). This was true for patients with and without pCR. CONCLUSIONS: In this large cohort of patients treated with NAC, outcomes were not negatively impacted by IML. We demonstrated that IML influences treatment selection but is not a poor prognostic indicator when treated with modern NAC and multidisciplinary disease management.

Validation of the RSClin risk calculator in the National Cancer Data Base.

BACKGROUND: Guidelines recommend the use of genomic assays such as OncotypeDx to aid in decisions regarding the use of chemotherapy for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. The RSClin prognostic tool integrates OncotypeDx and clinicopathologic features to predict distant recurrence and chemotherapy benefit, but further validation is needed before broad clinical adoption. METHODS: This study included patients from the National Cancer Data Base (NCDB) who were diagnosed with stage I-III HR+/HER2- breast cancer from 2010 to 2020 and received adjuvant endocrine therapy with or without chemotherapy. RSClin-predicted chemotherapy benefit was stratified into low (<3% reduction in distant recurrence), intermediate (3%-5%), and high (>5%). Cox models were used to model mortality adjusted for age, comorbidity index, insurance, and race/ethnicity. RESULTS: A total of 285,441 patients were identified for inclusion from the NCDB, with an average age of 60 years and a median follow-up of 58 months. Chemotherapy was associated with improved overall survival only for those predicted to have intermediate (adjusted hazard ratio [aHR], 0.68; 95% confidence interval [CI], 0.60-0.79) and high benefit per RSClin (aHR, 0.66; 95% CI, 0.61-0.72). Consistent benefit was seen in the subset with a low OncotypeDx score (<26) and intermediate (aHR, 0.66; 95% CI, 0.53-0.82) or high (aHR, 0.71; 95% CI, 0.58-0.86) RSClin-predicted benefit. No survival benefit with chemotherapy was seen in patients with a high OncotypeDx score (≥26) and low benefit per RSClin (aHR, 1.70; 95% CI, 0.41-6.99). CONCLUSIONS: RSClin may identify high-risk patients who benefit from treatment intensification more accurately than OncotypeDx, and further prospective study is needed.

Stress, Isolation, and Sleep Quality among Breast Cancer Survivors throughout the COVID-19 Pandemic: A Longitudinal Study in a Multi-Ethnic Cohort.

Purpose: This study examined how stress, isolation, and sleep quality were impacted throughout the COVID-19 pandemic among breast cancer survivors (BCS). Methods: BCS enrolled in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort were surveyed in 2020, 2021, and 2022. An 11-item isolation/stress score was repeatedly measured in each survey and its changes were examined through mixed-effects models. Sleep quality was assessed in 2022 by the Insomnia Severity Index (ISI). Results: In total, 1899 BCS responded (response rate: 62.8%), of whom 69% were White and 24% Black (median time since diagnosis: 5.1 years, IQR: 2.3-9.2). The isolation/stress score decreased significantly from 2020 to 2022 for White BCS, but only started declining for Black BCS in 2022. Consequently, although there were no significant racial difference in 2020, Black BCS had significantly higher isolation/stress scores in 2021 and 2022 (P < .01), while it became nonsignificant after adjusting for socioeconomic factors. BCS who were single, on Medicaid, without a high school degree, or with annual household income <$35,000 had significantly higher isolation/stress scores. Regarding sleep quality, 48% of BCS reported clinically-significant insomnia (ISI ≥ 8), and insomnia was strongly associated with higher isolation/stress scores (P-trend < .001). Conclusions: Our findings suggested that the isolation/stress level improved among BCS as the pandemic subsided, but this positive trend was not observed equally across racial/ethnic groups potentially due to lack of resources. Implications for Cancer Survivors: Additional resources, such as access to counseling services and sleep assistance programs, might support the post-pandemic recovery of undersevered BCS.

The impact of race and age on response to neoadjuvant therapy and long-term outcomes in Black and White women with early-stage breast cancer.

PURPOSE: There are a paucity of data and a pressing need to evaluate response to neoadjuvant chemotherapy (NACT) and determine long-term outcomes in young Black women with early-stage breast cancer (EBC). METHODS: We analyzed data from 2196 Black and White women with EBC treated at the University of Chicago over the last 2 decades. Patients were divided into groups based on race and age at diagnosis: Black women [Formula: see text] 40 years, White women [Formula: see text] 40 years, Black women [Formula: see text] 55 years, and White women [Formula: see text] 55 years. Pathological complete response rate (pCR) was analyzed using logistic regression. Overall survival (OS) and disease-free survival (DFS) were analyzed using Cox proportional hazard and piecewise Cox models. RESULTS: Young Black women had the highest risk of recurrence, which was 22% higher than young White women (p = 0.434) and 76% higher than older Black women (p = 0.008). These age/racial differences in recurrence rates were not statistically significant after adjusting for subtype, stage, and grade. In terms of OS, older Black women had the worst outcome. In the 397 women receiving NACT, 47.5% of young White women achieved pCR, compared to 26.8% of young Black women (p = 0.012). CONCLUSIONS: Black women with EBC had significantly worse outcomes compared to White women in our cohort study. There is an urgent need to understand the disparities in outcomes between Black and White breast cancer patients, particularly in young women where the disparity in outcome is the greatest.

The Impact of Race and Age on Response to Neoadjuvant Therapy and Long-Term Outcomes in Black and White Women with Early-Stage Breast Cancer.

PURPOSE: There are a paucity of data and a pressing need to evaluate response to neoadjuvant chemotherapy (NACT) and determine long-term outcomes in young Black women with early-stage breast cancer (EBC). METHODS: We analyzed data from 2,196 Black and White women with EBC treated at the University of Chicago over the last 2 decades. Patients were divided into groups based on race and age at diagnosis: Black women 40 years, White women 40 years, Black women 55 years, and White women 55 years. Pathological complete response rate (pCR) was analyzed using logistic regression. Overall survival (OS) and disease-free survival (DFS) were analyzed using Cox proportional hazard and piecewise Cox models. RESULTS: Young Black women had the highest risk of recurrence, which was 22% higher than young White women (p=0.434) and 76% higher than older Black women (p=0.008). These age/racial differences in recurrence rates were not statistically significant after adjusting for subtype, stage, and grade. In terms of OS, older Black women had the worst outcome. In the 397 women receiving NACT, 47.5% of young White women achieved pCR, compared to 26.8% of young Black women (p=0.012). CONCLUSIONS: Black women with EBC had significantly worse outcomes compared to White women in our cohort study. There is an urgent need to understand the disparities in outcomes between Black and White breast cancer patients, particularly in young women where the disparity in outcome is the greatest.

Racial Disparities in Pathological Complete Response Among Patients Receiving Neoadjuvant Chemotherapy for Early-Stage Breast Cancer.

Importance: Among patients with breast cancer, inconsistent findings have been published on racial disparities in achieving pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT). Objective: To investigate whether racial disparities exist in achieving pCR and what factors contribute to them. Design, Setting, and Participants: Within the ongoing Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), which consists of a prospectively ascertained cohort of patients with breast cancer, 690 patients with stage I to III breast cancer receiving NACT were identified for this single-institution study at the University of Chicago Medicine. Patients diagnosed between 2002 and 2020 (median follow-up: 5.4 years) were included; next-generation sequencing data on tumor-normal tissue pairs were available from 186 ChiMEC patients, including both primary and residual tumor samples. Statistical analysis was performed from September 2021 to September 2022. Exposures: Demographic, biological, and treatment factors that could contribute to disparities in achieving pCR. Main Outcomes and Measures: pCR was defined as the absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ. Results: The study included 690 patients with breast cancer, with a mean (SD) age of 50.1 (12.8) years. Among the 355 White patients, 130 (36.6%) achieved pCR compared to 77 of the 269 Black patients (28.6%; P = .04). Not achieving pCR was associated with significantly worse overall survival (adjusted hazard ratio, 6.10; 95% CI, 2.80-13.32). Black patients had significantly lower odds of achieving pCR compared with White patients in the hormone receptor-negative/ERBB2+ subtype (adjusted odds ratio, 0.30; 95% CI, 0.11-0.81). Compared with White patients with ERBB2+ disease, Black patients were more likely to have MAPK pathway alterations (30.0% [6 of 20] vs 4.6% [1 of 22]; P = .04), a potential mechanism of anti-ERBB2 therapy resistance. Tumor mutational burden and somatic alterations in several genes (eg, FGF4, FGF3, CCND1, MCL1, FAT1, ERCC3, PTEN) were significantly different between the primary and residual tumors. Conclusions and Relevance: In this cohort study of patients with breast cancer, racial disparities in response to NACT were associated with disparities in survival and varied across different breast cancer subtypes. This study highlights the potential benefits of better understanding the biology of primary and residual tumors.

Association of Residual Ductal Carcinoma In Situ With Breast Cancer Recurrence in the Neoadjuvant I-SPY2 Trial.

Importance: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS). Objective: To examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response. Design, Setting, and Participants: The study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence. Interventions: Participants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery. Main Outcomes and Measures: The presence of DCIS and EFS, DRFS, and LRR. Results: The study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS. Conclusions and Relevance: The analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS. Trial Registration: ClinicalTrials.gov Identifier NCT01042379.

High-Resolution Full-3D Specimen Imaging for Lumpectomy Margin Assessment in Breast Cancer.

BACKGROUND: Two-dimensional (2D) specimen radiography (SR) and tomosynthesis (DBT) for breast cancer yield data that lack high-depth resolution. A volumetric specimen imager (VSI) was developed to provide full-3D and thin-slice cross-sectional visualization at a 360° view angle. The purpose of this prospective trial was to compare VSI, 2D SR, and DBT interpretation of lumpectomy margin status with the final pathologic margin status of breast lumpectomy specimens. METHODS: The study enrolled 200 cases from two institutions. After standard imaging and interpretation was performed, the main lumpectomy specimen was imaged with the VSI device. Image interpretation was performed by three radiologists after surgery based on VSI, 2D SR, and DBT. A receiver operating characteristic (ROC) curve was created for each method. The area under the curve (AUC) was computed to characterize the performance of the imaging method interpreted by each user. RESULTS: From 200 lesions, 1200 margins were interpreted. The AUC values of VSI for the three radiologists were respectively 0.91, 0.90, and 0.94, showing relative improvement over the AUCs of 2D SR by 54%, 13%, and 40% and DBT by 32% and 11%, respectively. The VSI has sensitivity ranging from 91 to 94%, specificity ranging from 81 to 85%, a positive predictive value ranging from 25 to 30%, and a negative predicative value of 99%. CONCLUSIONS: The ROC curves of the VSI were higher than those of the other specimen imaging methods. Full-3D specimen imaging can improve the correlation between the main lumpectomy specimen margin status and surgical pathology. The findings from this study suggest that using the VSI device for intraoperative margin assessment could further reduce the re-excision rates for women with malignant disease.

Impact of post-diagnosis weight change on survival outcomes in Black and White breast cancer patients.

PURPOSE: To evaluate weight change patterns over time following the diagnosis of breast cancer and to examine the association of post-diagnosis weight change and survival outcomes in Black and White patients. METHODS: The study included 2888 women diagnosed with non-metastatic breast cancer in 2000-2017 in Chicago. Longitudinal repeated measures of weight and height were collected, along with a questionnaire survey including questions on body size. Multilevel mixed-effects models were used to examine changes in body mass index (BMI). Delayed entry Cox proportional hazards models were used to investigate the impacts of changing slope of BMI on survival outcomes. RESULTS: At diagnosis, most patients were overweight or obese with a mean BMI of 27.5 kg/m2 and 31.5 kg/m2 for Blacks and Whites, respectively. Notably, about 45% of the patients had cachexia before death and substantial weight loss started about 30 months before death. In multivariable-adjusted analyses, compared to stable weight, BMI loss (> 0.5 kg/m2/year) showed greater than 2-fold increased risk in overall survival (hazard ratio [HR] = 2.60, 95% CI 1.88-3.59), breast cancer-specific survival (HR = 3.05, 95% CI 1.91-4.86), and disease-free survival (HR = 2.12, 95% CI 1.52-2.96). The associations were not modified by race, age at diagnosis, and pre-diagnostic weight. BMI gain (> 0.5 kg/m2/year) was also related to worse survival, but the effect was weak (HR = 1.60, 95% CI 1.10-2.33 for overall survival). CONCLUSION: BMI loss is a strong predictor of worse breast cancer outcomes. Growing prevalence of obesity may hide diagnosis of cancer cachexia, which can occur in a large proportion of breast cancer patients long before death.

Racial disparities in survival outcomes among breast cancer patients by molecular subtypes.

PURPOSE: Differences in tumor biology, genomic architecture, and health care delivery patterns contribute to the breast cancer mortality gap between White and Black patients in the US. Although this gap has been well documented in previous literature, it remains uncertain how large the actual effect size of race is for different survival outcomes and the four breast cancer subtypes. METHODS: We established a breast cancer patient cohort at the University of Chicago Comprehensive Cancer Center. We chose five major survival outcomes to study: overall survival, recurrence-free survival, breast-cancer-specific survival, time-to-recurrence and post-recurrence survival. Cox proportional hazards models were used to estimate the hazard ratios between Black and White patients, adjusting for selected patient, tumor, and treatment characteristics, and also stratified by the four breast cancer subtypes. RESULTS: The study included 2795 stage I-III breast cancer patients (54% White and 38% Black). After adjusting for selected patient, tumor and treatment characteristics, Black patients still did worse than White patients in all five survival outcomes. The racial difference was highest within the HR-/HER2+ subgroup, in both overall survival (hazard ratio = 4.00, 95% CI 1.47-10.86) and recurrence-free survival (hazard ratio = 3.00, 95% CI 1.36-6.60), adjusting for age at diagnosis, cancer stage, and comorbidities. There was also a significant racial disparity within the HR+/HER2- group in both overall survival and recurrence-free survival. CONCLUSIONS: Our study confirmed that racial disparity existed between White and Black breast cancer patients in terms of both survival and recurrence, and found that this disparity was largest among HR-/HER2+ and HR+/HER2- patients.

Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial.

Importance: Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed. Objective: To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial. Design, Setting, and Participants: The I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016. Interventions: Participants were randomized to receive taxane- and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery. Main Outcomes and Measures: The primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial. Results: Of the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years' median follow-up). Conclusions and Relevance: When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.

MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2-Positive and/or Hormone Receptor-Negative Breast Cancers in the I-SPY 2 Trial.

PURPOSE: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer. PATIENTS AND METHODS: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week. RESULTS: MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). CONCLUSION: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

The Prognostic Value of the AJCC 8th Edition Staging System for Patients Undergoing Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND: The American Joint Committee on Cancer (AJCC) 8th edition staging system for breast cancer has been validated in the upfront surgery setting, but has not been examined for its prognostic impact on patients undergoing neoadjuvant chemotherapy. METHODS: The National Cancer Data Base was used to identify patients with invasive unilateral breast cancer from 2010 to 2015 who underwent neoadjuvant chemotherapy. AJCC clinical stage classification was compared between the 7th and 8th editions. Receiver operating characteristic analysis of Kaplan-Meier overall survival (OS) was used to determine the predictive fit of the 7th and 8th edition staging in estimating OS. RESULTS: AJCC 7th and 8th clinical staging assignments were applied to 57,466 patients who underwent neoadjuvant chemotherapy for stage I-III breast cancer from 2010 to 2015. Overall, 37.5% of patients were downstaged and 27.8% were upstaged from the 7th to the 8th edition classification. Kaplan-Meier curves comparing 7th and 8th edition staging differed in OS rates, with a mean follow-up time of 41.5 months. AJCC 8th edition prognostic staging was a better predictor of OS than 7th edition anatomic staging for both clinical stage [area under the curve (AUC) 0.67 vs. 0.62, p < 0.01] and pathological stage (AUC 0.70 vs. 0.66, p < 0.01). CONCLUSIONS: Sixty-five percent of patients have a shift in clinical stage in the AJCC 8th edition. AJCC 8th edition staging has better predictive value for OS than 7th edition staging. While validation of these findings with an independent dataset is needed, 8th edition staging will help improve prognostic modeling in patients undergoing neoadjuvant chemotherapy.

Erratum: Author Correction: Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

[This corrects the article DOI: 10.1038/s41523-018-0074-6.].

Intensive Surveillance with Biannual Dynamic Contrast-Enhanced Magnetic Resonance Imaging Downstages Breast Cancer in BRCA1 Mutation Carriers.

PURPOSE: To establish a cohort of high-risk women undergoing intensive surveillance for breast cancer.Experimental Design: We performed dynamic contrast-enhanced MRI every 6 months in conjunction with annual mammography (MG). Eligible participants had a cumulative lifetime breast cancer risk ≥20% and/or tested positive for a pathogenic mutation in a known breast cancer susceptibility gene. RESULTS: Between 2004 and 2016, we prospectively enrolled 295 women, including 157 mutation carriers (75 BRCA1, 61 BRCA2); participants' mean age at entry was 43.3 years. Seventeen cancers were later diagnosed: 4 ductal carcinoma in situ (DCIS) and 13 early-stage invasive breast cancers. Fifteen cancers occurred in mutation carriers (11 BRCA1, 3 BRCA2, 1 CDH1). Median size of the invasive cancers was 0.61 cm. No patients had lymph node metastasis at time of diagnosis, and no interval invasive cancers occurred. The sensitivity of biannual MRI alone was 88.2% and annual MG plus biannual MRI was 94.1%. The cancer detection rate of biannual MRI alone was 0.7% per 100 screening episodes, which is similar to the cancer detection rate of 0.7% per 100 screening episodes for annual MG plus biannual MRI. The number of recalls and biopsies needed to detect one cancer by biannual MRI were 2.8 and 1.7 in BRCA1 carriers, 12.0 and 8.0 in BRCA2 carriers, and 11.7 and 5.0 in non-BRCA1/2 carriers, respectively. CONCLUSIONS: Biannual MRI performed well for early detection of invasive breast cancer in genomically stratified high-risk women. No benefit was associated with annual MG screening plus biannual MRI screening.See related commentary by Kuhl and Schrading, p. 1693.

Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

Advances in the surgical management of the axilla in patients treated with neoadjuvant chemotherapy, especially those with node positive disease at diagnosis, have led to changes in practice and more judicious use of axillary lymph node dissection that may minimize morbidity from surgery. However, there is still significant confusion about how to optimally manage the axilla, resulting in variation among practices. From the viewpoint of drug development, assessment of response to neoadjuvant chemotherapy remains paramount and appropriate assessment of residual disease-the primary endpoint of many drug therapy trials in the neoadjuvant setting-is critical. Therefore decreasing the variability, especially in a multicenter clinical trial setting, and establishing a minimum standard to ensure consistency in clinical trial data, without mandating axillary lymph node dissection, for all patients is necessary. The key elements which include proper staging and identification of nodal involvement at diagnosis, and appropriately targeted management of the axilla at the time of surgical resection are presented. The following protocols have been adopted as standard procedure by the I-SPY2 trial for management of axilla in patients with node positive disease, and present a framework for prospective clinical trials and practice.

Lymph node wire localization post-chemotherapy: Towards improving the false negative sentinel lymph node biopsy rate in breast cancer patients.

PURPOSE: To evaluate whether the disease status of the pre-neoadjuvant chemotherapy (NAC) core biopsied lymph node (preNACBxLN) in patients with node positive breast cancer corresponds to nodal status of all surgically retrieved lymph nodes (LNs) post-NAC and whether wire localization of this LN is feasible. MATERIALS AND METHODS: HIPPA compliant IRB approved retrospective study including breast cancer patients (a.) with preNACBxLN confirmed metastases, (b.) who received NAC, and (c.) underwent wire localization of the preNACBxLN. Electronic medical records were reviewed. Fisher's exact test was used to compare differences in residual disease post-NAC among breast cancer subtypes. RESULTS: 28 women with node positive breast cancer underwent ultrasound guided wire localization of the preNACBxLN, without complication. There was no evidence of residual nodal disease for 16 patients, with mean 4.4 (median 4) LNs resected. 12 patients had residual nodal metastases, with mean 9.2 (median 7) LNs resected and mean 2.3 (median 2) LNs with tumor involvement. 11 patients had metastases detected within the localized LN. One patient had micrometastasis in a sentinel LN, despite no residual disease in the preNACBxLN. Patients with luminal A/B breast cancer more often had residual nodal metastases (86%) at pathology, as compared to patients with HER2+ (20%) and Triple Negative breast cancer (50%), though not quite achieving statistical significance (p=0.055). CONCLUSION: Ultrasound guided wire localization of the preNACBxLN is feasible and may improve detection of residual tumor in patients post-NAC.

Use of Postmastectomy Radiotherapy and Survival Rates for Breast Cancer Patients with T1-T2 and One to Three Positive Lymph Nodes.

BACKGROUND: The effectiveness of postmastectomy radiotherapy (PMRT) in terms of survival for breast cancer patients with American Joint Committee on Cancer (AJCC) pT1-2 and one to three tumor positive lymph nodes is controversial, especially in this era of more effective systemic treatment. METHODS: Using data from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) program between 1998 and 2008, this study respectively identified 93,793 and 36,299 women with AJCC pT1-2pN1 breast cancer who underwent mastectomy. The association of PMRT use with overall and cause-specific survival was examined using multivariable Cox models in subgroups defined by tumor stage. RESULTS: In the NCDB cohort, 21.5 % of the patients (n = 20,236) received PMRT, and a very similar percentage (21.9 %, n = 7939) received PMRT in the SEER cohort. In the NCDB cohort, PMRT was associated with a 14 % relative risk reduction in all-cause mortality among the patients with two positive lymph nodes and tumors 2-5 cm in size or three positive nodes [hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.81-0.91; p < 0.0001], but PMRT had no beneficial effect for the patients with one positive node or two positive nodes and tumors 2 cm in size or smaller. Analysis of the SEER cohort confirmed this heterogeneous effect, showing PMRT to be associated with a 14 % relative risk reduction in breast cancer cause-specific mortality among the patients with two positive nodes and tumors 2-5 cm in size or three positive nodes (HR 0.86; 95 % CI 0.77-0.96; p = 0.007) but not in the other subgroup. CONCLUSION: The effectiveness of radiotherapy depends on the combination comprising the number of positive lymph nodes and tumor size, which may enable more precise patient selection for PMRT.

Utilization of radiotherapy for malignant phyllodes tumors: analysis of the National Cancer Data Base, 1998-2009.

BACKGROUND: Malignant phyllodes tumors of the breast have traditionally been treated with surgical excision. Recently, the use of adjuvant radiotherapy has been advocated to reduce the risk of local recurrence; however, this recommendation is controversial in the absence of consistent outcome data. We hypothesize that there has been a trend toward increased utilization of adjuvant radiotherapy for malignant phyllodes tumors despite its uncertain effect on outcomes. METHODS: Using the National Cancer Data Base, predictors of radiotherapy utilization were examined for women with malignant phyllodes from 1998 to 2009. Kaplan-Meier and Cox regression models were generated to determine the effect of radiotherapy on local recurrence (LR), disease-free survival (DFS), and overall survival (OS). RESULTS: Of the 3,120 patients with malignant phyllodes, 57 % underwent breast conservation surgery and 42 % underwent mastectomy. Overall, 14.3 % of women received adjuvant radiotherapy. Utilization of radiotherapy doubled over the study period (9.5 % in 1998-1999 vs. 19.5 % in 2008-2009, p < 0.001). Women were significantly more likely to receive radiotherapy if they were diagnosed later in the study, were age 50-59 years old, had tumors >10 cm, or had lymph nodes removed. For the 1,774 patients with available recurrence data, overall recurrence was 14.1 %, and LR was 5.9 %. In adjusted models, adjuvant radiotherapy reduced LR (aHR 0.43, 95 % CI 0.19-0.95) but did not impact DFS or OS after 53 months' median follow-up. CONCLUSIONS: Utilization of adjuvant radiotherapy for malignant phyllodes doubled from 1998 to 2009. Radiotherapy significantly reduced LR but had no effect on DFS or OS.

Operative risks associated with contralateral prophylactic mastectomy: a single institution experience.

BACKGROUND: The purpose of this study was to determine if newly diagnosed breast cancer patients undergoing contralateral prophylactic mastectomy (CPM) experience more complications than patients undergoing unilateral mastectomy (UM). METHODS: A total of 600 patients underwent either UM or CPM between January 2009 and March 2012 for unilateral breast cancer. Operative complications were classified as minor (aspirations, infection requiring antibiotics, partial flap and nipple necrosis, minor bleeding, delayed wound healing) or major (hematoma or seroma requiring operation, infection requiring rehospitalization, blood product transfusion, total flap or nipple loss, implant removal), mixed (both minor and major complications), or multiple. Chi-square and multivariate logistic regressions were used for the analysis. RESULTS: Of the 600 patients, 391 (65 %) underwent UM and 209 (35 %) underwent CPM. Across all complication groups, there were significantly more complications in the CPM group versus the UM group (41.6 vs. 28.6 %, p = 0.001). Major complications alone were significantly greater in the CPM versus the UM group (13.9 vs. 4.1 %, p < 0.001). When adjusting for age, body mass index, smoking and diabetes history, AJCC stage, reconstruction, previous radiation therapy, and adjuvant therapy, CPM patients were 1.5 times more likely to have any complication (odds ratio [OR] 1.53; 95 % CI 1.04-2.25, p = 0.029) and 2.7 times more likely to have a major complication compared with UM patients (OR 2.66; 95 % CI 1.37-5.19, p = 0.004). CONCLUSIONS: CPM patients have an increased risk of complications, especially major complications requiring rehospitalization or reoperation. These complications may influence patient and physician decisions to choose CPM.