Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer.

Importance: National Comprehensive Cancer Network guidelines currently recommend germline testing for high-risk genes in selected patients with breast cancer. The clinical utility of recommending testing all patients with breast cancer with multigene panels is currently under consideration. Objective: To examine the implications of universal testing of patients with breast cancer with respect to clinical decision-making. Design, Setting, and Participants: Patients from a previously reported cohort were assessed as in-criteria or out-of-criteria according to the 2017 guidelines and underwent testing with a multigene germline panel between 2017 to 2018. Patients were women and men aged 18 to 90 years, with a new and/or previous diagnosis of breast cancer who had not undergone either single or multigene testing. Clinicians from 20 community and academic sites documented patient clinical information and changes to clinical recommendations made according to test findings. Association between prevalence of pathogenic or likely pathogenic germline variants and previously unreported clinical features, including scores generated by the BRCAPRO statistical model, was determined. Data were analyzed from April 2020 to May 2022. Exposure: New and/or previous diagnosis of breast cancer. Main Outcomes and Measures: Disease management recommendations that were changed as a result of genetic testing results are reported. Results: Clinicians were asked to assess changes to clinical management as a result of germline genetic testing for 952 patients. Informative clinician-reported recommendations were provided for 939 (467 in-criteria and 472 out-of-criteria) of the patients with breast cancer (936 [99.7%] female; 702 [74.8%] White; mean [SD] age at initial diagnosis, 57.6 [11.5] years). One or more changes were reported for 31 of 37 (83.8%) in-criteria patients and 23 of 34 (67.6%) out-of-criteria patients with a pathogenic or likely pathogenic variant. Recommendations were changed as a result of testing results for 14 of 22 (63.6%) out-of-criteria patients who had a variant in a breast cancer predisposition gene. Clinicians considered testing beneficial for two-thirds of patients with pathogenic or likely pathogenic variants and for one-third of patients with either negative results or variants of uncertain significance. There was no difference in variant rate between patients meeting the BRCAPRO threshold (≥10%) and those who did not (P = .86, Fisher exact test). No changes to clinical recommendations were made for most patients with negative results (345 of 349 patients [98.9%]) or variants of uncertain significance (492 of 509 patients [96.7%]). Conclusions and Relevance: In this cohort study, germline genetic testing was used by clinicians to direct treatment for most out-of-criteria patients with breast cancer with pathogenic or likely pathogenic germline variants, including those with moderate-risk variants. Universal germline testing informs clinical decision-making and provides access to targeted treatments and clinical trials for all patients with breast cancer.

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

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

Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle?

PURPOSE: An estimated 10% of breast and ovarian cancers result from hereditary causes. Current testing guidelines for germ line susceptibility genes in patients with breast carcinoma were developed to identify carriers of BRCA1/ 2 variants and have evolved in the panel-testing era. We evaluated the capability of the National Comprehensive Cancer Network (NCCN) guidelines to identify patients with breast cancer with pathogenic variants in expanded panel testing. METHODS: An institutional review board-approved multicenter prospective registry was initiated with 20 community and academic sites experienced in cancer genetic testing and counseling. Eligibility criteria included patients with a previously or newly diagnosed breast cancer who had not undergone either single- or multigene testing. Consecutive patients 18 to 90 years of age were consented and underwent an 80-gene panel test. Health Insurance Portability and Accountability Act-compliant electronic case report forms collected information on patient demographics, diagnoses, phenotypes, and test results. RESULTS: More than 1,000 patients were enrolled, and data records for 959 patients were analyzed; 49.95% met NCCN criteria, and 50.05% did not. Overall, 8.65% of patients had a pathogenic/likely pathogenic (P/LP) variant. Of patients who met NCCN guidelines with test results, 9.39% had a P/LP variant. Of patients who did not meet guidelines, 7.9% had a P/LP variant. The difference in positive results between these groups was not statistically significant (Fisher's exact test P = .4241). CONCLUSION: Our results indicate that nearly half of patients with breast cancer with a P/LP variant with clinically actionable and/or management guidelines in development are missed by current testing guidelines. We recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing.

Multigene Panel Testing Detects Equal Rates of Pathogenic BRCA1/2 Mutations and has a Higher Diagnostic Yield Compared to Limited BRCA1/2 Analysis Alone in Patients at Risk for Hereditary Breast Cancer.

BACKGROUND: Recently introduced multigene panel testing including BRCA1 and BRCA2 genes for hereditary cancer risk has raised concerns with the ability to detect all deleterious BRCA1/2 mutations compared to older methods of sequentially testing BRCA1/2 separately. The purpose of this study was to evaluate rates of pathogenic BRCA1/2 mutations and variants of uncertain significance (VUS) between previous restricted algorithms of genetic testing and newer approaches of multigene testing. METHODS: Data was collected retrospectively from 966 patients who underwent genetic testing at one of three sites from a single institution. Test results were compared between patients who underwent BRCA1/2 testing only (limited group, n = 629) to those who underwent multigene testing with 5-43 cancer-related genes (panel group, n = 337). RESULTS: Deleterious BRCA1/2 mutations were identified in 37 patients, with equivalent rates between limited and panel groups (4.0 vs. 3.6%, respectively, p = 0.86). Thirty-nine patients had a BRCA1/2 VUS, with similar rates between limited and panel groups (4.5 vs. 3.3%, respectively, p = 0.49). On multivariate analysis, there was no difference in detection of either BRCA1/2 mutations or VUS between both groups. Of patients undergoing panel testing, an additional 3.9 % (n = 13) had non-BRCA pathogenic mutations and 13.4% (n = 45) had non-BRCA VUSs. Mutations in PALB2, CHEK2, and ATM were the most common non-BRCA mutations identified. CONCLUSIONS: Multigene panel testing detects pathogenic BRCA1/2 mutations at equivalent rates as limited testing and increases the diagnostic yield. Panel testing increases the VUS rate, mainly as a result of non-BRCA genes. Patients at risk for hereditary breast cancer can safely benefit from up-front, more efficient, multigene panel testing.

Preliminary Results in 173 Breast Cancer Patients Treated with Post-Lumpectomy MammoSite Single-Lumen Brachytherapy or Multi-Catheter Brachytherapy.

The objective of this study was to report our single-institution results with MammoSite and multi-catheter brachytherapy. Between February 2003 and January 2009, 173 women with unifocal pathological Tis, T1, or T2 (up to 30 mm), N0 or N1 carcinomas of the breast were treated with post-lumpectomy brachytherapy to 34 Gy in 10 fractions over 5-10 days. We treated 137 patients with MammoSite single-lumen balloon brachytherapy, and 36 patients with multi-catheter brachytherapy. Patients with small and/or nonspherical lumpectomy cavities were usually treated with multi-catheter brachytherapy using 4-12 interstitial catheters. Median follow-up was 33 months. Three-year ipsilateral breast tumor control, disease-free, and overall survival rates for MammoSite brachytherapy were 100%, 100%, and 99%, respectively. Similar rates were obtained with multi-catheter brachytherapy. Minimum distances from the planning target volume for plan evaluation to a rib were 10 ± 8 mm (mean ± standard deviation) and 8 ± 4 mm (mean ± standard deviation) for MammoSite brachytherapy and multi-catheter brachytherapy, respectively (p = 0.48). Maximum rib doses were 101 ± 14% (mean ± standard deviation) and 74 ± 10% (mean ± standard deviation) of the prescribed dose for MammoSite brachytherapy and multi-catheter brachytherapy, respectively (p = 0.001). Multi-catheter brachytherapy results in more conformal radiation dose delivery and a significantly lower rib dose than MammoSite single-lumen brachytherapy. Long-term follow-up is needed to determine if the delivery of a lower radiation dose to the ribs will translate into a lower incidence of rib pain and fractures.

Results with accelerated partial breast irradiation in terms of estrogen receptor, progesterone receptor, and human growth factor receptor 2 status.

PURPOSE: To report our results with accelerated partial breast irradiation (APBI) in terms of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2/neu) status. METHODS AND MATERIALS: Between February 2003 and June 2009, 209 women with early-stage breast carcinomas were treated with APBI using multicatheter, MammoSite, or Contura brachytherapy to 34 Gy in 10 fractions twice daily over 5-7 days. Three patient groups were defined by receptor status: Group 1: ER or PR (+) and HER-2/neu (-) (n = 180), Group 2: ER and PR (-) and HER-2/neu (+) (n = 10), and Group 3: ER, PR, and HER-2/neu (-) (triple negative breast cancer, n = 19). Median follow-up was 22 months. RESULTS: Group 3 patients had significantly higher Scarff-Bloom-Richardson scores (p < 0.001). The 3-year ipsilateral breast tumor control rates for Groups 1, 2, and 3 were 99%, 100%, and 100%, respectively (p = 0.15). Group 3 patients tended to experience relapse in distant sites earlier than did non-Group 3 patients. The 3-year relapse-free survival rates for Groups 1, 2, and 3 were 100%, 100%, and 81%, respectively (p = 0.046). The 3-year cause-specific and overall survival rates for Groups 1, 2, and 3 were 100%, 100%, and 89%, respectively (p = 0.002). CONCLUSIONS: Triple negative breast cancer patients typically have high-grade tumors with significantly worse relapse-free, cause-specific, and overall survival. Longer follow-up will help to determine whether these patients also have a higher risk of ipsilateral breast tumor relapse.

Preliminary results with accelerated partial breast irradiation in high-risk breast cancer patients.

PURPOSE: To analyze prognostic factors in adequately staged breast cancer patients who were treated with accelerated partial breast irradiation (APBI). METHODS AND MATERIALS: Axillary staging was required for invasive carcinomas. Between February 2003 and June 2009, 204 women with early stage breast carcinomas were treated with APBI using multicatheter, MammoSite, or Contura brachytherapy to 34 Gy in 10 fractions 2 times per day. Six patient characteristics were examined for prognostic significance: (1) N stage, (2) estrogen receptor (ER) status, (3) histologic subtype, (4) margin status, (5) age, and (6) tumor size. The median followup was 22 months. RESULTS: There were three failures in the ipsilateral breast (all were elsewhere failures), one relapse in the axilla, and seven relapses at any site. The presence of positive axillary node(s) had a significant adverse effect on ipsilateral breast tumor control (p=0.045) and locoregional control (p=0.001). The presence of an ER (-) tumor had a significant adverse effect on relapse-free survival (p=0.04). CONCLUSIONS: The patients with positive axillary node(s) were at increased risk for failure elsewhere in the ipsilateral breast or axilla, and the patients with ER (-) tumors were at increased risk for relapse at any site. However, it is unclear whether the pN1 and ER (-) patients would have faired any better if they had received whole breast irradiation rather than APBI. We believe that the patients with positive axillary node(s) or ER (-) tumors should be treated on clinical trials to better define the role of APBI.

A Contura catheter offers dosimetric advantages over a MammoSite catheter that increase the applicability of accelerated partial breast irradiation.

PURPOSE: The purpose of this study was to determine whether a Contura catheter (SenoRx, Inc, Aliso Viejo, CA) can increase the applicability of accelerated partial breast irradiation. METHODS AND MATERIALS: One hundred eighty-two women with early stage breast carcinomas were treated with postlumpectomy brachytherapy using a Contura multilumen catheter (n=45) or a MammoSite single-lumen catheter (Cytyc Corp, Marlborough, MA) (n=137). Hypothetical MammoSite catheter treatment plans were created for the Contura patients. Treatment planning goals were to (1) avoid a radiation "hot spot" in the skin and (2) have only a small air/fluid pocket next to the balloon. RESULTS: The median followup was 16 months. Eighty-nine percent (40 of 45) of Contura plans satisfied both treatment planning goals vs. only 36% (16 of 45) of MammoSite plans (p<0.0001). A Contura catheter did not require explantation in 16% (7 of 45) of patients where balloon-to-skin spacing was only 3-6mm and 11% (5 of 45) of patients where there was an air/fluid pocket >10% of the planning target volume for plan evaluation (PTV_EVAL). A MammoSite catheter was explanted in 10% of cases where the minimum balloon-to-skin distance was <7mm and in 13% of cases where there was a large air/fluid pocket next to the balloon. Our incidence rates of acute toxicity with a Contura catheter were similar to those with a MammoSite catheter. CONCLUSIONS: A Contura catheter provides important dosimetric advantages over a MammoSite catheter and does not require explantation in cases where balloon-to-skin spacing is only 3-6mm or an air/fluid pocket next to the balloon is >10% of PTV_EVAL.