Genomic Characterization of Aggressive Breast Cancer in Younger Women.

PURPOSE: Although breast cancer (BC) risk increases with age, BC in younger women is more aggressive with higher mortality compared with older women. We characterize the genomic landscape of BCs in younger women. METHODS: Clinicopathologic, molecular, and genomic differences across age groups (< 40 years, 40-60 years, > 60 years) in female BC patients were investigated in two large cohorts [AACR-GENIE8.1 (n = 11,594) and METABRIC (n = 2509)]. Cox-proportional regression analyzed the prognostic impact of age groups for disease-specific survival (DSS) and recurrence-free survival (RFS) in METABRIC and progression-free survival (PFS) in GENIE cohorts. Chi-squared test was used to assess statistical associations between genomic alterations and age groups. RESULTS: Survival analysis showed that women < 40 years had shorter DSS [hazard ratio (HR): 1.52, p = 0.005], RFS (HR: 1.4, p = 0.006), and PFS (HR: 1.82, p = 0.0003) compared with women 40-60 years, and shorter RFS (HR: 1.5, p = 0.001) and PFS (HR: 2.95, p < 0.0001) compared with women > 60 years. Molecular subtypes in the METABRIC cohort showed women < 40 years were enriched with basal, and HER2+ subtypes, and less enriched with luminal A and B subtype (p < 0.0001). Characterization of genomic alterations in both cohorts demonstrated that BCs in women < 40 years were more enriched with TP53 mutations (FDR < 0.0001), BRCA1 mutations (FDR = 0.01), ERBB2 amplifications (FDR < 0.001), CDK12 amplifications (FDR < 0.001), and PPM1D amplifications (FDR < 0.001). In contrast, BCs in older women (> 60 years) were more enriched with PIK3CA, KMT2C, and CDH1 mutations (FDR < 0.0001). CONCLUSIONS: BCs in young women are associated with shorter survival and more aggressive genomic features, including mutations in TP53 and BRCA1, and amplifications in ERBB2 and CDK12. These findings have the potential to impact clinical trial design and treatment.

Looking Back: International Practice Patterns in Breast Radiation Oncology From a Case-Based Survey Across 54 Countries During the First Surge of the COVID-19 Pandemic.

PURPOSE: The COVID-19 pandemic has profoundly affected cancer care worldwide, including radiation therapy (RT) for breast cancer (BC), because of risk-based resource allocation. We report the evolution of international breast RT practices during the beginning of the pandemic, focusing on differences in treatment recommendations between countries. MATERIALS AND METHODS: Between July and November 2020, a 58-question survey was distributed to radiation oncologists (ROs) through international professional societies. Changes in RT decision making during the first surge of the pandemic were evaluated across six hypothetical scenarios, including the management of ductal carcinoma in situ (DCIS), early-stage, locally advanced, and metastatic BC. The significance of changes in responses before and during the pandemic was examined using chi-square and McNemar-Bowker tests. RESULTS: One thousand one hundred three ROs from 54 countries completed the survey. Incomplete responses (254) were excluded from the analysis. Most respondents were from the United States (285), Japan (117), Italy (63), Canada (58), and Brazil (56). Twenty-one percent (230) of respondents reported treating at least one patient with BC who was COVID-19-positive. Approximately 60% of respondents reported no change in treatment recommendation during the pandemic, except for patients with metastatic disease, for which 57.7% (636/1,103; P < .0005) changed their palliative practice. Among respondents who noted a change in their recommendation during the first surge of the pandemic, omitting, delaying, and adopting short-course RT were the most frequent changes, with most transitioning to moderate hypofractionation for DCIS and early-stage BC. CONCLUSION: Early in the COVID-19 pandemic, significant changes in global RT practice patterns for BC were introduced. The impact of published results from the FAST FORWARD trial supporting ultrahypofractionation likely confounded the interpretation of the pandemic's independent influence on RT delivery.

Endocrine Therapy for Primary and Secondary Prevention After Diagnosis of High-Risk Breast Lesions or Preinvasive Breast Cancer.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Patients with high-risk breast lesions (HRLs) or preinvasive breast cancers face an elevated risk of future breast cancer diagnoses. Endocrine therapy in this setting reduces the risk of a future diagnosis but does not confer improved survival, thus the side effects of primary/secondary prevention must be considered relative to the benefits. Here, we discuss the available chemoprevention regimens for patients with HRLs and considerations for selecting a regimen, as well as the decision making surrounding use of adjuvant endocrine therapy for patients with ductal carcinoma in situ (DCIS). For patients with HRLs, available chemoprevention regimens differ by menopausal status, including tamoxifen 20 mg once daily for 5 years and more recently tamoxifen 5 mg once daily for 3 years in both premenopausal and postmenopausal women as well as raloxifene or aromatase inhibitors for postmenopausal women. We recommend a shared decision-making approach with attention to patient preferences related to risk tolerance and side-effect profiles. Low-dose tamoxifen appears to be a particularly favorable choice that is well tolerated, without risk of serious adverse events and offers comparable risk reduction to other regimens. For DCIS, the benefit of endocrine therapy in addition to radiation is small, and appears to be driven mainly by a reduction in contralateral breast diagnoses or new breast cancers. A strategy that reduces the side-effect profile of chemoprevention such as low-dose tamoxifen may be especially appealing in the setting of secondary prevention.

Regional Disparities in the Use and Delivery of Adjuvant Radiation Therapy after Lumpectomy for Breast Cancer in the Medicare Population.

Purpose: We examined radiation therapy (RT) use among patients with early-stage breast cancer and analyzed the contribution of patient, cancer, and regional factors to the likelihood of RT receipt across Health Service Areas. Methods and Materials: We identified 13,176 patients aged 66 to 79 years in the Surveillance, Epidemiology, and End Results (SEER) Program-Medicare database who were diagnosed with lymph node-negative breast cancer in 2007 to 2011 and were treated with breast-conserving surgery. Patients were stratified as being at high risk or low risk for recurrence based on National Comprehensive Cancer Network Guidelines. Receipt of RT was studied with 5 modeling approaches to determine whether RT use and regional variation in its use changed based on the risk level of the cohort. Multivariable mixed-effects logistic regression was performed for each outcome. Choropleth maps were used to describe patterns of RT use. Results: Among high-risk patients, 70.1% received RT, compared with 72.6% of low-risk patients (P = .002). Among patients receiving RT, 60.9% were classified as high-risk, compared with 63.0% of patients who did not receive RT (P = .002). In multivariable analyses, patients in all rural areas had lower odds of receiving RT compared with the entire cohort (odds ratio [OR], 0.73; P < .001) and had lower odds of being high-risk and receiving RT (OR, 0.69; P < .001). Black patients (OR, 0.73; P = .001) and Asian patients (OR, 0.74; P = .004) had decreased likelihood of receiving RT compared with the entire cohort. The regional interclass correlation coefficient (ICC) for the model predicting receipt of RT among all patients was 0.05 and among low-risk patients was 0.06. The regional ICC dropped to 0.02 for the model predicting being both high-risk and receiving RT among all patients. Conclusions: We observed regional and racial and ethnic disparities in RT receipt among our cohort. Reassuringly, less regional variability was observed for RT receipt among those at high risk for recurrence. Future work is needed to understand the causes of these regional disparities to better serve patients who may benefit from treatment.

Prediction Models and Decision Aids for Women with Ductal Carcinoma In Situ: A Systematic Literature Review.

Even though Ductal Carcinoma in Situ (DCIS) can potentially be an invasive breast cancer (IBC) precursor, most DCIS lesions never will progress to IBC if left untreated. Because we cannot predict yet which DCIS lesions will and which will not progress, almost all women with DCIS are treated by breast-conserving surgery +/- radiotherapy, or even mastectomy. As a consequence, many women with non-progressive DCIS carry the burden of intensive treatment without any benefit. Multiple decision support tools have been developed to optimize DCIS management, aiming to find the balance between over- and undertreatment. In this systematic review, we evaluated the quality and added value of such tools. A systematic literature search was performed in Medline(ovid), Embase(ovid), Scopus and TRIP. Following the PRISMA guidelines, publications were selected. The CHARMS (prediction models) or IPDAS (decision aids) checklist were used to evaluate the tools' methodological quality. Thirty-three publications describing four decision aids and six prediction models were included. The decision aids met at least 50% of the IPDAS criteria. However, most lacked tools to facilitate discussion of the information with healthcare providers. Five prediction models quantify the risk of an ipsilateral breast event after a primary DCIS, one estimates the risk of contralateral breast cancer, and none included active surveillance. Good quality and external validations were lacking for all prediction models. There remains an unmet clinical need for well-validated, good-quality DCIS risk prediction models and decision aids in which active surveillance is included as a management option for low-risk DCIS.

Integration of Radiation and Reconstruction After Mastectomy.

Postmastectomy radiation therapy (PMRT) is a mainstay of local therapy for many breast cancer patients. Patients undergoing mastectomy typically are offered options for breast reconstruction. For patients who are candidates for PMRT, there are ongoing challenges with combining optimal radiation technique to prioritize oncologic outcomes, against the goals of minimizing toxicity and achieving the best reconstruction outcomes. The process by which these decisions are made continues to evolve as surgical and radiation techniques have improved and expanded, and as more patients with different risk profiles for local recurrence are receiving PMRT. We review the considerations regarding the different types of reconstruction and timing with radiation treatment. We also review the technical radiation consideration such as dose-fractionation, use of bolus and scar boost, exploring the controversies associated with the nuanced decisions regarding radiation and reconstructive surgery which are influenced by variables that are under continued investigation.

Breast cancer awareness among Afghan refugee women in Turkey.

Background Refugees and asylum-seekers have lower levels of cancer awareness and this contributes to low rates of screening and more advanced cancers at diagnosis, compared to non-refugee populations, due largely to reduced access to medical information and care. The global Afghan refugee population is rapidly increasing with the ongoing Afghan political crisis. The present study investigates breast cancer (BC) awareness among Afghan refugee women. Methods: A cross-sectional survey of Afghan refugee women residing in Turkey was performed in September 2021. A validated BC patient awareness assessment, the Breast Cancer Awareness Measure (BCAM), was used to assess participants' knowledge of seven domains of BC: symptoms, self-examination, ability to notice breast changes, age-related risk of BC, urgency of addressing changes in the breast, BC risk factors, and BC screening. BCAM was translated into patients' native language and administered verbally by a physician with the assistance of an official interpreter. Routine statistical methods were employed for data analysis. Findings: A total of 430 patients were recruited to the study. The response rate was 97·7% (420 patients). The median participant age was 35 years (range: 18 to 68 years). The majority of participants (84%) had no formal education. Most participants (96%) were married, and most (95%) were not employed. Awareness of warning signs of BC was low: only seven to 18% of participants recognized 11 common warning signs of BC. Participant use of breast self-exam (BSE) was low, with 82% of participants stating they rarely or never complete BSE. Zero of 420 patients reported ever seeing a physician for a change in their breasts. Awareness of risk factors for BC was also low: only 15% of participants recognized increasing age as a risk factor for BC, and other risk factors were only recognized by four to 39% of participants. Interpretation: BC awareness among Afghan refugee women is critically low. There is an urgent need to target this population for practical interventions to increase BC awareness, in addition to screening and earlier diagnosis. Evidence-based interventions include educational sessions in patients' native language and use of BSE and clinical breast examination for screening. Funding: American Society for Radiation Oncology (ASTRO) - Association of Residents in Radiation Oncology (ARRO) Global Health Scholar Grant, Dana-Farber Cancer Institute Jay Harris Junior Faculty Research Grant.

Natural History and Characteristics of ERBB2-mutated Hormone Receptor-positive Metastatic Breast Cancer: A Multi-institutional Retrospective Case-control Study from AACR Project GENIE.

PURPOSE: We wanted to determine the prognosis and the phenotypic characteristics of hormone receptor-positive advanced breast cancer tumors harboring an ERBB2 mutation in the absence of a HER2 amplification. EXPERIMENTAL DESIGN: We retrospectively collected information from the American Association of Cancer Research-Genomics Evidence Neoplasia Information Exchange registry database from patients with hormone receptor-positive, HER2-negative, ERBB2-mutated advanced breast cancer. Phenotypic and co-mutational features, as well as response to treatment and outcome were compared with matched control cases ERBB2 wild type. RESULTS: A total of 45 ERBB2-mutant cases were identified for 90 matched controls. The presence of an ERBB2 mutation was not associated with worse outcome determined by overall survival (OS) from first metastatic relapse. No significant differences were observed in phenotypic characteristics apart from higher lobular infiltrating subtype in the ERBB2-mutated group. ERBB2 mutation did not seem to have an impact in response to treatment or time-to-progression (TTP) to endocrine therapy compared with ERBB2 wild type. In the co-mutational analyses, CDH1 mutation was more frequent in the ERBB2-mutated group (FDR < 1). Although not significant, fewer co-occurring ESR1 mutations and more KRAS mutations were identified in the ERBB2-mutated group. CONCLUSIONS: ERBB2-activating mutation was not associated with a worse OS from time of first metastatic relapse, or differences in TTP on treatment as compared with a series of matched controls. Although not significant, differences in coexisting mutations (CDH1, ESR1, and KRAS) were noted between the ERBB2-mutated and the control group.

Geospatial Disparities in the Treatment of Curable Breast Cancer Across the US.

IMPORTANCE: Patient factors help explain disparities in breast cancer treatments and outcomes. OBJECTIVE: To determine the extent to which geospatial variation in initial breast cancer care can be attributed to region vs patient factors with the aim of guiding quality improvement efforts. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective population-based cohort study from January 1, 2007, through December 31, 2016, using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database that included 31 571 patients diagnosed with stage I to III breast cancer from 2007 through 2013. Five metrics of care delivery were defined: stage I at diagnosis, chemotherapy receipt, radiation therapy receipt, endocrine therapy (ET) initiation (year 1), and ET continuation (years 3-5). Data analysis was performed from January to June 2021. EXPOSURES: Stage I diagnosis and treatment with chemotherapy, radiation therapy, or ET. MAIN OUTCOMES AND MEASURES: For each metric, total variance was attributed proportionally to 4 domains-random, patient factors (eg, age, race and ethnicity, socioeconomic status), region (health service area [HSA]), and unexplained-using hierarchical multivariable modeling. RESULTS: Of 31 571 total patients (median [IQR] age, 71 [68-75] years), 19 391 (61.4%) had stage I disease at diagnosis. Among eligible patients, 17 297 of 21 190 (81.6%) received radiation therapy, 7204 of 9903 (72.8%) received chemotherapy, 13 115 of 26 855 (48.8%) initiated ET, and 13 944 of 26 855 (52.1%) continued ET. Geospatial density (ie, heat) maps highlight regional performance patterns. For all 5 metrics, region/HSA explained more observed variation (24%-48%) than patient factors (1%-4%); the largest share of variation was unexplained (35%-54%). The metrics with the largest proportion of total variance attributed to region/HSA were ET initiation and continuation (28% and 39%, respectively). CONCLUSIONS AND RELEVANCE: In this cohort study, there was substantial unexplained geospatial variation in initial breast cancer care. The variance attributed to region/HSA was multifold larger than that explained by patient factors. The importance of patient factors such as race and ethnicity notwithstanding, future quality improvement efforts should focus on reducing unwarranted geospatial variation, especially including optimizing the delivery of ET in low-performing regions.

A Phase 1 Dose-Escalation Trial of Radiation Therapy and Concurrent Cisplatin for Stage II and III Triple-Negative Breast Cancer.

PURPOSE: Patients with triple-negative breast cancer (TNBC) experience higher local-regional recurrence rates than those with luminal or HER2-positive tumors. This prospective, phase 1B trial was designed to assess the safety and to establish the maximum tolerated dose (MTD) of cisplatin with radiation therapy for women with early-stage TNBC. METHODS AND MATERIALS: Eligible patients had stage II or III TNBC. Cisplatin was initiated at 10 mg/m2 intravenously once weekly during radiation and then escalated in a 3 + 3 design by 10 mg/m2 at each dose level until 40 mg/m2, or the MTD, was reached. Patients undergoing breast-conserving therapy (BCT) or mastectomy were accrued in separate parallel cohorts during dose escalation, followed by a 10-patient expansion at the MTD. RESULTS: During 2013 to 2018, 55 patients were accrued. Four patients developed dose-limiting toxicity. In the BCT cohort, 1 patient receiving 40 mg/m2 developed tinnitus resulting in a cisplatin delay; therefore, this was the BCT cohort MTD. In the mastectomy cohort, 1 patient receiving 20 mg/m2 developed a grade 3 urinary infection, and 2 additional patients had dose-limiting toxicities at 40 mg/m2 (grade 3 neutropenia and grade 2 tinnitus), both resulting in cisplatin delay. Thus, 30 mg/m2 was the mastectomy cohort MTD. Median follow-up was 48.5 months. Three-year disease-free survival was 74.7% for the BCT cohort and 64.4% for the mastectomy cohort. CONCLUSIONS: Adjuvant radiation therapy with concurrent cisplatin is feasible with a recommended phase 2 dose of 30 mg/m2 and 40 mg/m2 intravenously weekly in mastectomy and BCT cohorts, respectively.

Deep-learning system to improve the quality and efficiency of volumetric heart segmentation for breast cancer.

Although artificial intelligence algorithms are often developed and applied for narrow tasks, their implementation in other medical settings could help to improve patient care. Here we assess whether a deep-learning system for volumetric heart segmentation on computed tomography (CT) scans developed in cardiovascular radiology can optimize treatment planning in radiation oncology. The system was trained using multi-center data (n = 858) with manual heart segmentations provided by cardiovascular radiologists. Validation of the system was performed in an independent real-world dataset of 5677 breast cancer patients treated with radiation therapy at the Dana-Farber/Brigham and Women's Cancer Center between 2008-2018. In a subset of 20 patients, the performance of the system was compared to eight radiation oncology experts by assessing segmentation time, agreement between experts, and accuracy with and without deep-learning assistance. To compare the performance to segmentations used in the clinic, concordance and failures (defined as Dice < 0.85) of the system were evaluated in the entire dataset. The system was successfully applied without retraining. With deep-learning assistance, segmentation time significantly decreased (4.0 min [IQR 3.1-5.0] vs. 2.0 min [IQR 1.3-3.5]; p < 0.001), and agreement increased (Dice 0.95 [IQR = 0.02]; vs. 0.97 [IQR = 0.02], p < 0.001). Expert accuracy was similar with and without deep-learning assistance (Dice 0.92 [IQR = 0.02] vs. 0.92 [IQR = 0.02]; p = 0.48), and not significantly different from deep-learning-only segmentations (Dice 0.92 [IQR = 0.02]; p ≥ 0.1). In comparison to real-world data, the system showed high concordance (Dice 0.89 [IQR = 0.06]) across 5677 patients and a significantly lower failure rate (p < 0.001). These results suggest that deep-learning algorithms can successfully be applied across medical specialties and improve clinical care beyond the original field of interest.

Association between the 21-gene recurrence score and isolated locoregional recurrence in stage I-II, hormone receptor-positive breast cancer.

BACKGROUND: Although the 21-gene recurrence score (RS) assay is widely used to predict distant recurrence risk and benefit from adjuvant chemotherapy among women with hormone receptor-positive (HR+) breast cancer, the relationship between the RS and isolated locoregional recurrence (iLRR) remains poorly understood. Therefore, we examined the association between the RS and risk of iLRR for women with stage I-II, HR+ breast cancer. METHODS: We identified 1758 women captured in the national prospective Breast Cancer-Collaborative Outcomes Research Database who were diagnosed with stage I-II, HR+ breast cancer from 2006 to 2012, treated with mastectomy or breast-conserving surgery, and received RS testing. Women who received neoadjuvant therapy were excluded. The association between the RS and risk of iLRR was examined using competing risks regression. RESULTS: Overall, 19% of the cohort (n = 329) had a RS ≥25. At median follow-up of 29 months, only 22 iLRR events were observed. Having a RS ≥25 was not associated with a significantly higher risk of iLRR compared to a RS < 25 (hazard ratio 1.14, 95% confidence interval 0.39-3.36, P = 0.81). When limited to women who received adjuvant endocrine therapy without chemotherapy (n = 1199; 68% of the cohort), having a RS ≥25 (n = 74) was significantly associated with a higher risk of iLRR compared to a RS < 25 (hazard ratio 3.66, 95% confidence interval 1.07-12.5, P = 0.04). In this group, increasing RS was associated with greater risk of iLRR (compared to RS < 18, hazard ratio of 1.66, 3.59, and 7.06, respectively, for RS 18-24, 25-30, and ≥ 31; Ptrend = 0.02). CONCLUSIONS: The RS was significantly associated with risk of iLRR in patients who did not receive adjuvant chemotherapy. The utility of the RS in identifying patients who have a low risk of iLRR should be further studied.

Location as Destiny: Identifying Geospatial Disparities in Radiation Treatment Interruption by Neighborhood, Race, and Insurance.

PURPOSE: Radiation therapy interruption (RTI) worsens cancer outcomes. Our purpose was to benchmark and map RTI across a region in the United States with known cancer outcome disparities. METHODS AND MATERIALS: All radiation therapy (RT) treatments at our academic center were cataloged. Major RTI was defined as ≥5 unplanned RT appointment cancellations. Univariate and multivariable logistic and linear regression analyses identified associated factors. Major RTI was mapped by patient residence. A 2-sided P value <.0001 was considered statistically significant. RESULTS: Between 2015 and 2017, a total of 3754 patients received RT, of whom 3744 were eligible for analysis: 962 patients (25.8%) had ≥2 RT interruptions and 337 patients (9%) had major RTI. Disparities in major RTI were seen across Medicaid versus commercial/Medicare insurance (22.5% vs 7.2%; P < .0001), low versus high predicted income (13.0% vs 5.9%; P < .0001), Black versus White race (12.0% vs 6.6%; P < .0001), and urban versus suburban treatment location (12.0% vs 6.3%; P < .0001). On multivariable analysis, increased odds of major RTI were seen for Medicaid patients (odds ratio [OR], 3.35; 95% confidence interval [CI], 2.25-5.00; P < .0001) versus those with commercial/Medicare insurance and for head and neck (OR, 3.74; 95% CI, 2.56-5.46; P < .0001), gynecologic (OR, 3.28; 95% CI, 2.09-5.15; P < .0001), and lung cancers (OR, 3.12; 95% CI, 1.96-4.97; P < .0001) compared with breast cancer. Major RTI was mapped to urban, majority Black, low-income neighborhoods and to rural, majority White, low-income regions. CONCLUSIONS: Radiation treatment interruption disproportionately affects financially and socially vulnerable patient populations and maps to high-poverty neighborhoods. Geospatial mapping affords an opportunity to correlate RT access on a neighborhood level to inform potential intervention strategies.

Cost Effectiveness of DCISionRT for Guiding Treatment of Ductal Carcinoma in Situ.

The DCISionRT test estimates the risk of an ipsilateral breast event (IBE) in patients with ductal carcinoma in situ (DCIS) as well as the benefit of adjuvant radiation therapy (RT). We determined the cost-effectiveness of DCISionRT using a Markov model simulating 10-year outcomes for 60-year-old women with DCIS based on nonrandomized data. Three strategies were compared: no testing, no RT (strategy 1); test all, RT for elevated risk only (strategy 2); and no testing, RT for all (strategy 3). We used utilities and costs from the literature and Medicare claims to determine incremental cost-effectiveness ratios and examined the number of women irradiated per IBE prevented. In the base-case scenario, strategy 1 was the cost-effective strategy. Strategy 2 was cost-effective compared with strategy 3 when the cost of DCISionRT was less than $4588. The number irradiated per IBE prevented were 8.37 and 15.46 for strategies 2 and 3, respectively, relative to strategy 1.