Jennifer L. Caswell Jin

Background: Immune activation is central to response to HER2-targeted therapy in HER2-positive breast cancer; however, early and scalable biomarkers that capture this biology remain limited. Methods: We developed a predictive model that used early dynamic changes in routinely obtained peripheral blood absolute lymphocyte count (ALC) alongside standard clinical and pathologic features to predict pathologic complete response (pCR) after neoadjuvant therapy in HER2-positive breast cancer. Results: In a discovery cohort of patients with stage I–III HER2-positive breast cancer treated per routine care with trastuzumab-based neoadjuvant therapy (n = 154), higher baseline ALC and greater decline in ALC after the first cycle were independently associated with increased likelihood of pCR (p < 0.001 for both). A predictive model using these two ALC variables alongside age, percentage of cells expressing estrogen receptor, progesterone receptor status, HER2 immunohistochemistry score, and tumor stage, demonstrated strong discrimination: the area under the curve (AUC) in the discovery cohort was 0.86, and 0.82 in a separate validation cohort (n = 83). In the validation cohort, the pCR rate was 12% among patients in the discovery model-predicted quartile with lowest pCR probability, 33% in the second quartile, 69% in the third quartile, and 79% in the highest probability quartile. Conclusion: These findings suggest that early measures of peripheral blood ALC, alongside standard clinical and pathologic features, offer a simple, scalable biomarker for anticipating response to HER2-targeted neoadjuvant therapy, with potential utility for early treatment adaptation and trial stratification.

This guideline has been updated. This ASCO Living Guideline is reviewed on an eight-week cycle. Please see the online dynamic version for the latest updates. Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and Appendix 2 (online only) for more. Purpose: To provide recommendations on use of medical therapies for patients with stage I to III hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. Methods: An Expert Panel including patient representation completed a systematic review of the evidence and formulated recommendations for practice. Eligible studies included patients with stage I to III hormone receptor–positive, HER2-negative breast cancer and evaluated neoadjuvant or adjuvant chemotherapy, endocrine therapy (ET), immunotherapy, or targeted therapy. Outcomes of interest included pathologic complete response, disease-free survival, distant recurrence-free survival, overall survival, health-related quality of life, and treatment-related adverse effects. Results: Forty-five randomized clinical trials (68 references) published from 2018 to 2026 were identified by the broad literature search. Supplemental searches identified six individual patient data meta-analyses and 21 retrospective studies that, combined with the primary clinical trials, informed guidance on which patients should receive treatment, which treatments should be selected, optimal treatment timing, duration of treatment, and approaches to support adherence. A final section addresses estimation of prognosis and treatment benefit to inform decisions across all phases of treatment. Recommendations: The recommendations are organized to follow the longitudinal care of patients with stage I to III hormone receptor–positive, HER2-negative breast cancer, reflecting the sequence of decisions faced by clinicians from diagnosis through completion of systemic therapy. ET remains the foundation of treatment for stage I to III hormone receptor–positive, HER2-negative breast cancer. For selected patients, chemotherapy and targeted therapies can further reduce the risk of recurrence and breast cancer death. Treatment recommendations should integrate clinicopathologic features, genomic assays, patient preferences, treatment tolerability, and estimated recurrence risk. The guideline provides evidence-based recommendations to support individualized treatment selection and sequencing across the continuum of care. Additional information is available on the ASCO Publications website .

PURPOSE: Germline testing is underutilized and varies by cancer diagnosis. We hypothesized that patient and clinician involvement in cascade testing of relatives varies by the cancer susceptibility (breast v gastrointestinal [GI]) of the affected gene. METHODS: All patients diagnosed with cancer in Georgia or California during 2018-2019 and reported to SEER registries, who were linked to a pathogenic variant (PV) result from testing laboratories, were surveyed 4.5 years postdiagnosis about (1) clinician involvement in result communication to relatives, (2) attitudes about result communication, (3) result communication to relatives, and (4) relatives' testing. PVs were categorized by primary association with breast ( BRCA1, BRCA2, ATM, BARD1, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53 ) or GI cancers ( MLH1, MSH2, MSH6, PMS2, EPCAM, APC, BMPR1A, CDKN2A, GREM1, POLD1, POLE, SMAD4 ). RESULTS: A total of 4,080 patients were surveyed; 2,183 responded (53.5%). Most had PVs associated with breast (83.4%) versus GI cancers (16.6%). Most (85.0%) reported a genetic counseling visit. Genetic counselors were most involved in encouraging family communication (71.5%, v oncologists 33.4%, surgeons 19.4%), advising how to talk with relatives (55.0%, versus oncologists 18.0%, surgeons 9.1%), and talking directly with relatives (33.4%, v oncologists 12.6%, surgeons 7.0%). Most patients considered sharing results their responsibility (86.8%); they notified 86.8% of first-degree and 44.9% of second-degree relatives. Nearly one third (29.0%) of patients reported that no relative was tested, whereas 18.3% reported that four or more relatives were tested. Outcomes did not differ by affected gene or cancer type ( P > .1). CONCLUSION: Patients with cancer are motivated to communicate PV results to relatives. However, few clinicians are involved and relatives' testing remains low. Novel care delivery models are needed to advance cascade testing and precision risk reduction.

PURPOSE: Advances in breast cancer treatment have reduced mortality and toxicity, but it remains unclear which patients receive updated care and when. We aimed to identify factors associated with receiving updated breast cancer care. METHODS: We analyzed patients age 65-85 years with local or regional breast cancer, diagnosed between 2010 and 2018, using the SEER-Medicare database. We included patients who were continuously enrolled in Medicare for 1 year after diagnosis and were eligible for one of four updated treatments: (1) adjuvant paclitaxel-trastuzumab (APT) for human epidermal growth factor receptor 2 (HER2)–positive local disease, (2) pertuzumab for HER2-positive regional disease, (3) neoadjuvant chemotherapy for triple-negative or HER2-positive regional disease, and (4) omission of chemotherapy for hormone receptor–positive, HER2-negative regional disease. We examined the association between treating oncologist specialization (percent of SEER-Medicare patients with breast cancer) and receipt of updated care using multivariable analysis. RESULTS: Of the 21,575 patients eligible for one of these four updated care approaches, use of the APT regimen increased from 30% (95% CI, 23% to 37%) to 72% (95% CI, 67% to 77%), pertuzumab from 0% to 71% (95% CI, 66% to 76%), neoadjuvant chemotherapy from 23% (95% CI, 18% to 28%) to 60% (95% CI, 56% to 65%), and omission of chemotherapy from 54% (95% CI, 52% to 57%) to 61% (95% CI, 59% to 64%) from 2010 to 2018. In multivariable analyses, higher median income of residence county and greater specialization of treating oncologist were statistically significantly associated with receipt of updated care for all four treatment scenarios. Patients from lower-income areas who received care from more specialized oncologists were as likely to receive updated care as those from higher-income areas. CONCLUSION: Patients from lower-income areas were less likely to receive updated care, but specialized oncologists helped mitigate this disparity. Care models that expand consultative access to specialized oncologists should be prioritized for evaluation.

Guideline‐concordant care in triple‐negative breast cancer was associated with improved survival, including from nonbreast cancer causes. This editorial explores what broader patient and health system influences, beyond treatment, are captured by guideline concordance.

There are limited prospective data on whether established risk factors modify breast cancer risk in women with pathogenic variants (PV) in BRCA1/2 and virtually no risk modification data for ATM, CHEK2, or PALB2. We conducted a nested case–control study in the Women’s Health Initiative (WHI), randomly selecting women with and without breast cancer for DNA sequencing. We evaluated breast cancer odds associated with obesity, family cancer history, smoking, alcohol, parity, breastfeeding, oophorectomy, tubal ligation, neighborhood socioeconomic status, and menopausal hormone therapy (MHT) with estrogen and progestin or estrogen only in PV carriers and noncarriers. In exploratory analyses, we grouped genes by established predisposition for estrogen receptor (ER)-positive (ATM and CHEK2) or ER-negative (BRCA1 and PALB2) disease. Multivariable models with interaction terms were used to assess differential risk modification by PVs. Among 12,957 WHI participants, 287 carried PVs. Breastfeeding was modestly associated with reduced risk for PALB2 [OR = 0.08; 95% confidence interval (CI), 0.00–0.92; P value = 0.042]. With one-sided 95% CI, power was sufficient to exclude OR ≥2.0 with obesity for ATM and BRCA2; smoking and alcohol for CHEK2; no breastfeeding for ATM; no oophorectomy for BRCA2 and CHEK2; no tubal ligation for CHEK2; and neighborhood socioeconomic status for all genes. Estrogen + progestin MHT was modestly associated with increased risk for ER-positive PVs (OR = 7.31; 95% CI, 1.14–64.20; P = 0.036). PVs did not modify risk (interaction P ≥ 0.05). BRCA1/2, ATM, CHEK2, and PALB2 PV carriers do not have breast cancer OR ≥2.0 with many established risk factors. However, MHT warrants additional study in PV carriers.Significance:There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.

PURPOSE: Clinical guidelines recommend offering individualized physical activity prescriptions to cancer survivors. However, there are limited tools to support individualized physical activity discussions and prescriptions. We developed and validated a simulation model–based tool to estimate individualized survival outcomes for postdiagnosis physical activity among postmenopausal breast cancer survivors. METHODS: We adapted an established simulation modeling approach developed within the Cancer Intervention and Surveillance Modeling Network to estimate breast cancer–specific and all-cause survival associated with postdiagnosis physical activity for 50- to 75-year-old (postmenopausal) women with stage I to III invasive breast cancer. Model estimates were generated for 60,480 subgroups based on age, weight status (BMI), stage, tumor subtype, treatment, aerobic (<30 min/wk [no/minimal], ≥30 to <150 min/wk [insufficient], ≥150 to <300 min/wk [active], ≥300 min/wk [highly active]), and muscle-strengthening (<2 or ≥2 d/wk) activity. The outcomes were 10-year survival and absolute survival benefits for different levels of physical activity by individual characteristics and treatment. Model inputs were derived from trials, cohort studies, registry, and surveillance data. External validation used independent data. RESULTS: Survival rates and absolute benefits for physical activity varied by age, weight status, stage, tumor subtype, and amount and type of activity. For example, the 10-year breast cancer–specific and all-cause survival for no/minimal activity in a 65- to 69-year-old-woman with stage II, hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer with obesity was 79.2% and 72.2%, respectively. Increasing aerobic activity from no/minimal to insufficient activity with <2 d/wk of muscle-strengthening was associated with absolute increases in 10-year breast cancer–specific and all-cause survival by 2.8 and 3.4 percentage points, respectively. The model closely replicated survival rates in independent data. CONCLUSION: Simulation model–based estimates could support clinical tools for guideline-recommended individualized discussions and physical activity prescriptions for breast cancer survivors.