Citations

Importance Many patients are diagnosed with atypical lesions or lobular carcinoma in situ (LCIS); however, evidence- and consensus-based guidelines for the management of many of these lesions are limited. Observations The American Society of Breast Surgeons, in collaboration with the Society of Breast Imaging and College of American Pathology, assembled a steering group to create guidelines for the management of atypical lesions and LCIS, inclusive of flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), classic LCIS (C-LCIS), and the variant LCIS forms pleomorphic LCIS (P-LCIS) and florid LCIS (F-LCIS). The natural history of ADH, ALH, and C-LCIS suggests that these lesions are associated with an elevated future breast cancer risk; therefore, patients diagnosed with these lesions should be recommended to undergo comprehensive risk assessment and counseling about breast cancer risk-reducing strategies. The magnitude of future breast cancer risk associated with P-LCIS and F-LCIS remains uncertain, yet if these lesions are determined to be hormone receptor positive, risk-reducing medications should be considered. There is no evidence that FEA is associated with an elevated future breast cancer risk. A second pathology review confirmation is recommended for ADH, should be considered for FEA, and is not necessary for ALH or LCIS. Currently available evidence supports the need to diagnostically excise most ADH, P-LCIS, and F-LCIS cases identified on core biopsy, although some ADH cases fulfilling strict criteria and multidisciplinary consensus can be observed. P-LCIS and F-LCIS require a negative margin, but ADH does not. ALH and C-LCIS can be safely observed if the core biopsy diagnosis is concordant with imaging features (ie, radiographic-pathologic concordance is established). Provided radiologic-pathologic concordance is confirmed, diagnostic excision is generally not indicated after a diagnosis of FEA alone. Conclusions and Relevance These guidelines provide evidence-informed, consensus-based recommendations for the management of atypical lesions of the breast, including ADH, ALH, FEA, C-LCIS, P-LCIS, and F-LCIS. Practicing clinicians who treat patients with atypical breast lesions or LCIS should consider integrating these guidelines into clinical management.

Although structured reporting of adverse events related to medical therapies is a critical aspect of clinical trials, the current practice fails to capture postoperative complications accurately or systematically, which precludes our ability to fully assess the impact of the risks of surgical interventions on oncologic outcomes. The incorporation of standardized, procedure‐specific definitions and severity classifications for postoperative complications into adverse event reporting in trials conducted through the National Clinical Trials Network is proposed.

PURPOSE To develop recommendations for germline mutation testing for patients with breast cancer. METHODS An ASCO–Society of Surgical Oncology (SSO) panel convened to develop recommendations based on a systematic review and formal consensus process. RESULTS Forty-seven articles met eligibility criteria for the germline mutation testing recommendations; 18 for the genetic counseling recommendations. RECOMMENDATIONS BRCA1/ 2 mutation testing should be offered to all newly diagnosed patients with breast cancer ≤65 years and select patients >65 years based on personal history, family history, ancestry, or eligibility for poly(ADP-ribose) polymerase (PARP) inhibitor therapy. All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered BRCA1/ 2 testing, regardless of family history. BRCA1/ 2 testing should be offered to women who develop a second primary cancer in the ipsilateral or contralateral breast. For patients with prior history of breast cancer and without active disease, testing should be offered to patients diagnosed ≤65 years and selectively in patients diagnosed after 65 years, if it will inform personal and family risk. Testing for high-penetrance cancer susceptibility genes beyond BRCA1/ 2 should be offered to those with supportive family histories; testing for moderate-penetrance genes may be offered if necessary to inform personal and family cancer risk. Patients should be provided enough pretest information for informed consent; those with pathogenic variants should receive individualized post-test counseling. Variants of uncertain significance should not impact management, and patients with such variants should be followed for reclassification. Referral to providers experienced in clinical cancer genetics may help facilitate patient selection and interpretation of expanded testing, and provide counseling of individuals without pathogenic germline variants but with significant family history. Additional information is available at www.asco.org/breast-cancer-guidelines .

ImportancePatients should have an active role in decisions about pursuing or forgoing specific therapies in treatment de-escalation trials.ObjectiveTo evaluate longitudinal patient-reported outcomes (PROs) encompassing decisional comfort and health-related quality of life (HRQOL) among patients who elected to enroll in a clinical trial evaluating radiotherapy alone, without breast surgery, for invasive breast cancers with exceptional response to neoadjuvant systemic therapy (NST).Design, Setting, and ParticipantsProspective, single-group, phase 2 clinical trial at 7 US medical centers. Women aged 40 years or older with invasive cT1-2 N0-1 M0 triple-negative or human epidermal growth factor receptor 2 (ERBB2)–positive breast cancer with no pathologic evidence of residual disease following standard NST enrolled from March 6, 2017, to November 9, 2021. Validated PRO measures were administered at baseline and 6, 12, and 36 months post-radiotherapy. Data were analyzed from January to February 2023.InterventionsPRO measures included the Decision Regret Scale (DRS), Functional Assessment of Cancer Therapy—Lymphedema (FACT-B+4), and Breast Cancer Treatment Outcomes Scale (BCTOS).Main Outcomes and MeasuresChanges in PRO measure scores and subscores over time.ResultsAmong 31 patients, the median (IQR) age was 61 (56-66) years, 26 (84%) were White, and 26 (84%) were non-Hispanic. A total of 15 (48%) had triple-negative disease and 16 (52%) had ERBB2-positive disease. Decisional comfort was high at baseline (median [IQR] DRS score 10 [0-25] on a 0-100 scale, with higher scores indicating higher decisional regret) and significantly increased over time (median [IQR] DRS score at 36 months, 0 [0-20]; P < .001). HRQOL was relatively high at baseline (median [IQR] FACT-B composite score 121 [111-134] on a 0-148 scale, with higher scores indicating higher HRQOL) and significantly increased over time (median [IQR] FACT-B score at 36 months, 128 [116-137]; P = .04). Perceived differences between the affected breast and contralateral breast were minimal at baseline (median [IQR] BCTOS score 1.05 [1.00-1.23] on a 1-4 scale, with higher scores indicating greater differences) and increased significantly over time (median [IQR] BCTOS score at 36 months, 1.36 [1.18-1.64]; P < .001). At 36 months postradiotherapy, the cosmetic subscore was 0.45 points higher than baseline (95% CI, 0.16-0.74; P = .001), whereas function, pain, and edema subscores were not significantly different than baseline.Conclusions and RelevanceIn this nonrandomized phase 2 clinical trial, analysis of PROs demonstrated an overall positive experience for trial participants, with longitudinal improvements in decisional comfort and overall HRQOL over time and minimal lasting adverse effects of therapy.Trial RegistrationClinicalTrials.gov Identifier: NCT02945579

Abstract Purpose: To evaluate prediction of response and event-free survival (EFS) following neoadjuvant endocrine therapy by SET2,3 index of nonproliferation gene expression related to estrogen and progesterone receptors adjusted for baseline prognosis. Experimental Design: A correlative study was conducted of SET2,3 measured from gene expression profiles of diagnostic tumor (Agilent microarrays) in 379 women with cStage II–III breast cancer from the American College of Surgeons Oncology Group Z1031 neoadjuvant aromatase inhibitor trial SET2,3 was dichotomized using the previously published cutoff. Fisher exact test was used to assess the association between SET2,3 and low proliferation at week 2–4 [Ki67 ≤ 10% or complete cell-cycle arrest (CCCA; Ki67 ≤ 2.7%)] and PEPI-0 rate in cohort B, and the association between SET2,3 and ypStage 0/I in all patients. Cox models were used to assess EFS with respect to SET2,3 excluding cohort B patients who switched to chemotherapy. Results: Patients with high SET2,3 had higher rate of pharmacodynamic response than patients with low SET2,3 (Ki67 ≤ 10% in 88.2% vs. 56.9%, P < 0.0001; CCCA in 50.0% vs. 26.2%, P = 0.0054), but rate of ypStage 0/I (24.0% vs. 20.4%, P = 0.4580) or PEPI = 0 (28.4% vs. 20.6%, P = 0.3419) was not different. Patients with high SET2,3 had longer EFS than patients with low SET2,3 (HR, 0.52, 95% confidence interval: 0.34–0.80; P = 0.0026). Conclusions: This exploratory analysis of Z1031 data demonstrated a higher rate of pharmacodynamic suppression of proliferation and longer EFS in high SET2,3 disease relative to low SET2,3 disease. The ypStage 0/I rate and PEPI = 0 rate were similar with respect to SET2,3.

580 Background: Patients (pts) in Cohort A of the American College of Surgeons Oncology Group Z1031 (Alliance) trial of NET for cStage II-III breast cancer were randomized to anastrozole [ANA], letrozole [LET] or exemestane [EXE] for 16-18 weeks (wks). In Cohort B, pts chose between ANA and LET and switched to chemotherapy or surgery if a tumor biopsy after 2-4 wks of NET had Ki67 >10%. Treatments after surgery were not defined by the trial protocol. SET2,3 measures nonproliferation gene expression related to estrogen and progesterone receptors adjusting for a baseline prognostic index that combines clinical tumor and nodal stage and a 4-gene molecular subtype (RNA4) defined by ESR1, PGR, ERBB2 and AURKA. High SET2,3 in a pre-treatment biopsy using cStage information is defined as SET2,3 >1.77. Methods: 379 pts had gene expression data from a research tumor biopsy prior to NET (Agilent 44K microarrays). A bioinformatician blinded to pt treatment and clinical outcomes determined SET2,3. The trial statistician then examined the association between SET2,3 and pharmacodynamic response at 2-4 wks (N=141, Cohort B): Ki67 ≤10% and complete cell cycle arrest (CCCA Ki67 ≤2.7%); pathologic outcomes in pts who completed NET: ypStage 0/1 (N=329, Cohorts A&B), PEPI-0 rate (N=155, Cohort B); and event-free survival (EFS) post-registration (N=244, Cohorts A&B). We used Fisher’s exact tests to assess whether responses, and Cox modeling to evaluate whether EFS, differed with respect to SET2,3 status. Results: High SET2,3 in 48% of pts (183/379) was associated with older age (median: 66 vs 63 years; p=0.012); cStage II (95% vs 75%; p <0.001); and pre-NET Ki67 ≤10% (37% vs 20%; p< 0.001) in pts with low SET2,3. In Cohort B, pts with high SET2,3 had a higher rate of pharmacodynamic response in their tumor at wk 2-4 than pts with low SET2,3 (Table). In the subset of Cohort B pts with wk 2-4 Ki67 ≤10%, pre-treatment SET2,3 trended numerically higher in pts who achieved PEPI-0 score (p=0.049) but the proportion achieving PEPI-0 did not differ by SET2,3 high/low status (Table). EFS was significantly longer for pts with high SET2,3 than pts with low SET2,3 (HR[H/L]: 0.52; 95% CI: 0.34-0.80; p=0.003). Conclusions: An exploratory analysis of Z1031 data demonstrated that the rate of pharmacodynamic suppression of proliferation by NET at 2-4 wks was greater and EFS was longer for pts with breast cancer expressing high SET2,3 disease than pts with low SET2,3. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Clinical trial information: NCT00265759. [Table: see text]

Abstract Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and toxicity limits use of these agents. Vitamin D is a potential prevention therapy for both ER+ and ER− disease and is safe with few side effects. This study evaluates the effect of 1-year of vitamin D supplementation on mammographic density (MD), a biomarker of breast cancer risk in a multicenter randomized controlled trial. Premenopausal women with ≥25% MD and no history of cancer were randomly assigned to 2,000 international units (IU) of vitamin D or placebo orally daily for 1 year. Change in percent MD was evaluated using Cumulus software after all participants completed treatment. Three hundred women enrolled between January 2011 and December 2013 with a mean age of 43 and diverse ethnicity [14% Hispanic, 12% African American (AA)]. Supplementation significantly increased vitamin D levels compared with placebo (14.5 ng/mL vs. −1.6 ng/mL; P &lt; 0.0001) with all participants on the vitamin D arm achieving vitamin D sufficiency at 12 months. Vitamin D was safe and well tolerated. After adjustment for baseline MD, the mean between-arm difference (vitamin D vs. placebo) at 1 year was −0.75 (−0.26, 1.76; P = 0.56). A greater effect was seen for women with ≥50% MD and AA women, although neither reached significance. This randomized controlled trial demonstrated significant improvement in vitamin D levels with 2,000 IU for 1 year, with 100% of supplemented women achieving sufficiency. However, a null effect was seen regarding change in MD for premenopausal women (the primary outcome of the study). Prevention Relevance: Current therapies for breast cancer prevention only prevent estrogen receptor positive (ER+) disease and are underutilized due to toxicity and side effects. Vitamin D is a potential prevention therapy for both ER+ and ER− disease and is safe with few side effects.

PURPOSE To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes. METHODS The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process. RESULTS Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria. RECOMMENDATIONS Patients with newly diagnosed BC and BRCA1/ 2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1/ 2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1/ 2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/ 2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines .

PURPOSE Primary endocrine therapy for ductal carcinoma in situ (DCIS) as a potential alternative to surgery has been understudied. This trial explored the feasibility of a short-term course of letrozole and sought to determine whether treatment results in measurable radiographic and biologic changes in estrogen receptor (ER)–positive DCIS. PATIENTS AND METHODS A phase II single-arm multicenter cooperative-group trial was conducted in postmenopausal patients diagnosed with ER-positive DCIS without invasion. Patients were treated with letrozole 2.5 mg per day for 6 months before surgery. Breast magnetic resonance imaging (MRI) was obtained at baseline, 3 months, and 6 months. The primary end point was change in 6-month MRI enhancement volume compared with baseline. RESULTS Overall, 79 patients were enrolled and 70 completed 6 months of letrozole. Of these, 67 patients had MRI data available for each timepoint. Baseline MRI volumes ranged from 0.004 to 26.3 cm 3 . Median reductions from baseline MRI volume (1.4 cm 3 ) were 0.6 cm 3 (61.0%) at 3 months ( P < .001) and 0.8 cm 3 (71.7%) at 6 months ( P < .001). Consistent reductions were seen in median baseline ER H-score (228; median reduction, 15.0; P = .005), progesterone receptor H-score (15; median reduction, 85.0; P < .001), and Ki67 score (12%; median reduction, 6.3%; P = .007). Of the 59 patients who underwent surgery per study protocol, persistent DCIS remained in 50 patients (85%), invasive cancer was detected in six patients (10%), and no residual DCIS or invasive cancer was seen in nine patients (15%). CONCLUSIONS In a cohort of postmenopausal women with ER-positive DCIS, preoperative letrozole resulted in significant imaging and biomarker changes. These findings support future trials of extended endocrine therapy as primary nonoperative treatment of some DCIS.

Purpose The American College of Surgeons Oncology Group Z1071 trial reported a 12.6% false-negative rate (FNR) for sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy (NAC) in cN1 disease. Patients were not selected for surgery based on response, but a secondary end point was to determine whether axillary ultrasound (AUS) after NAC after fine-needle aspiration cytology can identify abnormal nodes and guide patient selection for SLN surgery. Patients and Methods Patients with T0-4, N1-2, M0 breast cancer underwent AUS after neoadjuvant chemotherapy. AUS images were centrally reviewed and classified as normal or suspicious lymph nodes. AUS findings were tested for association with pathologic nodal status and SLN FNR. The impact of AUS results to select patients for SLN surgery to reduce the FNR was assessed. Results Postchemotherapy AUS images were reviewed for 611 patients. One hundred thirty (71.8%) of 181 AUS-suspicious patients were node positive at surgery compared with 243 (56.5%) of 430 AUS-normal patients (P < .001). Patients with AUS-suspicious nodes had a greater number of positive nodes and greater metastasis size (P < .001). The SLN FNR was not different based on AUS results; however, using a strategy where only patients with normal AUS undergo SLN surgery would potentially reduce the FNR in Z1071 patients with ≥ two SLNs removed from 12.6% to 9.8% when preoperative AUS results are considered as part of SLN surgery. Conclusion AUS is recommended after chemotherapy to guide axillary surgery. An FNR of 9.8% with the combination of AUS and SLN surgery would be acceptable for the adoption of SLN surgery for women with node-positive breast cancer treated with neoadjuvant chemotherapy.