A plain language summary of the TROPiCS-02 study in patients with breast cancer (HR-positive/HER2-negative).

WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment for certain types of advanced or metastatic breast cancer. One common type of breast cancer has at least 1 of 2 hormone receptors (HR positive) and does not have human epidermal growth factor 2 (HER2 negative). The HR and HER2 receptors are known to influence how severe a case of breast cancer is. Certain treatments will only work if a specific receptor is present on breast cancer cells. HR-positive/HER2-negative advanced or metastatic breast cancer can be treated with sacituzumab govitecan. This is a summary of the results of the TROPiCS-02 study. This study compared sacituzumab govitecan with standard chemotherapy in participants with HR-positive/HER2-negative advanced or metastatic breast cancer. WHAT WERE THE RESULTS?: The study showed that participants treated with sacituzumab govitecan lived significantly longer without their cancer getting worse than participants treated with chemotherapy. Participants also survived significantly longer and their tumors became significantly smaller in more participants treated with sacituzumab govitecan than with chemotherapy. In general, participants treated with sacituzumab govitecan were more likely to have side effects and had more severe side effects. These side effects included low levels of a type of white blood cell known as neutrophils and diarrhea. Oncologists (doctors that treat cancer) know of these side effects as they are common among people being treated for cancer. Doctors can control these side effects by following standard treatment guidelines and the package insert for sacituzumab govitecan. Participants treated with sacituzumab govitecan maintained their sense of well-being and ability to do daily activities (quality of life) longer than participants treated with chemotherapy. It also took longer for fatigue and other symptoms of cancer to worsen in participants treated with sacituzumab govitecan compared with chemotherapy. WHAT DO THE RESULTS MEAN?: Sacituzumab govitecan is more effective than standard chemotherapies for people who have already received multiple treatments for HR-positive/ HER2-negative advanced breast cancer. The side effects from sacituzumab govitecan could generally be managed well by doctors. Although there were more side effects with sacituzumab govitecan than with chemotherapy, they were generally mild to moderate.

Summary of quality of life in the ASCENT phase 3 clinical trial for people with metastatic triple-negative breast cancer.

WHAT IS THIS SUMMARY ABOUT?: A medicine called sacituzumab govitecan (brand name TRODELVY®) has been proven to be an effective treatment for metastatic triple-negative breast cancer (mTNBC for short). Metastatic breast cancer is cancer that has spread to other parts of the body. In mTNBC, the breast cancer cells do not have 3 common proteins on the cell surface, called receptors. mTNBC is more difficult to treat and more likely to come back than other types of breast cancer. The ASCENT study showed that participants with mTNBC treated with sacituzumab govitecan had a higher likelihood of living longer and delayed progression (worsening) of their cancer than those treated with standard chemotherapy. Here, we summarize the quality of life of participants with mTNBC in the ASCENT study. We compared quality of life between 236 participants treated with sacituzumab govitecan and 183 participants treated with standard chemotherapy. All participants previously received 2 or more chemotherapies that no longer controlled their cancer. WHAT ARE THE KEY TAKEAWAYS?: This analysis showed that participants treated with sacituzumab govitecan had better overall quality of life than participants treated with standard chemotherapy. They also had better "physical functioning", which is the ability to walk and do physical activities. Participants treated with sacituzumab govitecan maintained their overall quality of life for a longer time than those treated with standard chemotherapy. Participants treated with sacituzumab govitecan had less pain and were less tired than those treated with standard chemotherapy. On the other hand, participants treated with sacituzumab govitecan had worse diarrhea (loose or watery stools) and were more likely to have nausea/vomiting (feel sick or throw up) than participants treated with standard chemotherapy. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: Participants treated with sacituzumab govitecan had a higher likelihood of living longer and delayed progression (worsening) of their cancer. Participants also had a better overall quality of life, which was maintained (did not get worse) for a longer time. However, they experienced worsening of diarrhea and/or nausea/vomiting.Clinical Trial Registration: NCT02574455 (ASCENT) (ClinicalTrials.gov).

Effect of Electronic Symptom Monitoring on Patient-Reported Outcomes Among Patients With Metastatic Cancer: A Randomized Clinical Trial.

Importance: Electronic systems that facilitate patient-reported outcome (PRO) surveys for patients with cancer may detect symptoms early and prompt clinicians to intervene. Objective: To evaluate whether electronic symptom monitoring during cancer treatment confers benefits on quality-of-life outcomes. Design, Setting, and Participants: Report of secondary outcomes from the PRO-TECT (Alliance AFT-39) cluster randomized trial in 52 US community oncology practices randomized to electronic symptom monitoring with PRO surveys or usual care. Between October 2017 and March 2020, 1191 adults being treated for metastatic cancer were enrolled, with last follow-up on May 17, 2021. Interventions: In the PRO group, participants (n = 593) were asked to complete weekly surveys via an internet-based or automated telephone system for up to 1 year. Severe or worsening symptoms triggered care team alerts. The control group (n = 598) received usual care. Main Outcomes and Measures: The 3 prespecified secondary outcomes were physical function, symptom control, and health-related quality of life (HRQOL) at 3 months, measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference [MCID], 2-7 for physical function; no MCID defined for symptom control or HRQOL). Results on the primary outcome, overall survival, are not yet available. Results: Among 52 practices, 1191 patients were included (mean age, 62.2 years; 694 [58.3%] women); 1066 (89.5%) completed 3-month follow-up. Compared with usual care, mean changes on the QLQ-C30 from baseline to 3 months were significantly improved in the PRO group for physical function (PRO, from 74.27 to 75.81 points; control, from 73.54 to 72.61 points; mean difference, 2.47 [95% CI, 0.41-4.53]; P = .02), symptom control (PRO, from 77.67 to 80.03 points; control, from 76.75 to 76.55 points; mean difference, 2.56 [95% CI, 0.95-4.17]; P = .002), and HRQOL (PRO, from 78.11 to 80.03 points; control, from 77.00 to 76.50 points; mean difference, 2.43 [95% CI, 0.90-3.96]; P = .002). Patients in the PRO group had significantly greater odds of experiencing clinically meaningful benefits vs usual care for physical function (7.7% more with improvements of ≥5 points and 6.1% fewer with worsening of ≥5 points; odds ratio [OR], 1.35 [95% CI, 1.08-1.70]; P = .009), symptom control (8.6% and 7.5%, respectively; OR, 1.50 [95% CI, 1.15-1.95]; P = .003), and HRQOL (8.5% and 4.9%, respectively; OR, 1.41 [95% CI, 1.10-1.81]; P = .006). Conclusions and Relevance: In this report of secondary outcomes from a randomized clinical trial of adults receiving cancer treatment, use of weekly electronic PRO surveys to monitor symptoms, compared with usual care, resulted in statistically significant improvements in physical function, symptom control, and HRQOL at 3 months, with mean improvements of approximately 2.5 points on a 0- to 100-point scale. These findings should be interpreted provisionally pending results of the primary outcome of overall survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03249090.

A National Study of the Use of Asymptomatic Systemic Imaging for Surveillance Following Breast Cancer Treatment (AFT-01).

BACKGROUND: Although not guideline recommended, studies suggest 50% of locoregional breast cancer patients undergo systemic imaging during follow-up, prompting its inclusion as a Choosing Wisely measure of potential overuse. Most studies rely on administrative data that cannot delineate scan intent (prompted by signs/symptoms vs. asymptomatic surveillance). This is a critical gap as intent is the only way to distinguish overuse from appropriate care. OBJECTIVE: Our aim was to assess surveillance systemic imaging post-breast cancer treatment in a national sample accounting for scan intent. METHODS: A stage-stratified random sample of 10 women with stage II-III breast cancer in 2006-2007 was selected from each of 1217 Commission on Cancer-accredited facilities, for a total of 10,838 patients. Registrars abstracted scan type (computed tomography [CT], non-breast magnetic resonance imaging, bone scan, positron emission tomography/CT) and intent (cancer-related vs. not, asymptomatic surveillance vs. not) from medical records for 5 years post-diagnosis. Data were merged with each patient's corresponding National Cancer Database record, containing sociodemographic and tumor/treatment information. RESULTS: Of 10,838 women, 30% had one or more, and 12% had two or more, systemic surveillance scans during a 4-year follow-up period. Patients were more likely to receive surveillance imaging in the first follow-up year (lower proportions during subsequent years) and if they had estrogen receptor/progesterone receptor-negative tumors. CONCLUSIONS: Locoregional breast cancer patients undergo asymptomatic systemic imaging during follow-up despite guidelines recommending against it, but at lower rates than previously reported. Providers appear to use factors that confer increased recurrence risk to tailor decisions about systemic surveillance imaging, perhaps reflecting limitations of data on which current guidelines are based. ClinicalTrials.gov Identifier: NCT02171078.

Listeria monocytogenes wall teichoic acid decoration in virulence and cell-to-cell spread.

Wall teichoic acid (WTA) comprises a class of glycopolymers covalently attached to the peptidoglycan of gram positive bacteria. In Listeria monocytogenes, mutations that prevent addition of certain WTA decorating sugars are attenuating. However, the steps required for decoration and the pathogenic process interrupted are not well described. We systematically examined the requirement for WTA galactosylation in a mouse oral-virulent strain by first creating mutations in four genes whose products conferred resistance to a WTA-binding bacteriophage. WTA biochemical and structural studies indicated that galactosylated WTA was directly required for bacteriophage adsorption and that mutant WTA lacked appreciable galactose in all except one mutant - which retained a level ca. 7% of the parent. All mutants were profoundly attenuated in orally infected mice and were impaired in cell-to-cell spread in vitro. Confocal microscopy of cytosolic mutants revealed that all expressed ActA on their cell surface and formed actin tails with a frequency similar to the parent. However, the mutant tails were significantly shorter - suggesting a defect in actin based motility. Roles for the gene products in WTA galactosylation are proposed. Identification and interruption of WTA decoration pathways may provide a general strategy to discover non-antibiotic therapeutics for gram positive infections. © 2016 John Wiley & Sons Ltd.

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

PURPOSE: A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). METHODS: A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. RECOMMENDATIONS: The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

TBCRC 057: Survey about willingness to participate in cancer clinical trials during the pandemic.

BACKGROUND: Breast cancer patients experienced heightened anxiety during the pandemic. Also, modifications to clinical trial activities allowing for virtual platforms, local assessments, and greater flexibility were introduced to facilitate participation. We sought to evaluate the association between pandemic-related anxiety and willingness to participate in trials and how pandemic-era modifications to trial activities affect the decision to participate. METHODS: We conducted an online survey from August to September, 2021 of patients with breast cancer assessing pandemic-related anxiety; clinical trials knowledge and attitudes; willingness to participate during and before the pandemic; and how each modification affects the decision to participate. Fisher's exact tests evaluated differences in proportions and two-sample t-tests evaluated differences in means. The association of pandemic-related anxiety with a decline in willingness to participate during compared to prior to the pandemic was modeled using logistic regression. RESULTS: Among 385 respondents who completed the survey, 81% reported moderate-severe pandemic-related anxiety. Mean willingness to participate in a trial was lower during the pandemic than prior [2.97 (SD 1.17) vs. 3.10 (SD 1.09), (p < 0.001)]. Severe anxiety was associated with higher odds of diminished willingness to participate during the pandemic compared to prior (OR 5.07). Each of the modifications, with the exception of opting out of research-only blood tests, were endorsed by >50% of respondents as strategies that would increase their likelihood of deciding to participate. CONCLUSIONS: While pandemic-related anxiety was associated with diminished willingness to participate in trials, the leading reasons for reluctance to consider trial participation were unrelated to the pandemic but included worries about not getting the best treatment, side effects, and delaying care. Patients view trial modifications favorably, supporting continuation of these modifications, as endorsed by the National Cancer Institute and others.

Partial Breast Irradiation for Patients With Early-Stage Invasive Breast Cancer or Ductal Carcinoma In Situ: An ASTRO Clinical Practice Guideline.

PURPOSE: This guideline provides evidence-based recommendations on appropriate indications and techniques for partial breast irradiation (PBI) for patients with early-stage invasive breast cancer and ductal carcinoma in situ. METHODS: ASTRO convened a task force to address 4 key questions focused on the appropriate indications and techniques for PBI as an alternative to whole breast irradiation (WBI) to result in similar rates of ipsilateral breast recurrence (IBR) and toxicity outcomes. Also addressed were aspects related to the technical delivery of PBI, including dose-fractionation regimens, target volumes, and treatment parameters for different PBI techniques. The guideline is based on a systematic review provided by the Agency for Healthcare Research and Quality. Recommendations were created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. RESULTS: PBI delivered using 3-dimensional conformal radiation therapy, intensity modulated radiation therapy, multicatheter brachytherapy, and single-entry brachytherapy results in similar IBR as WBI with long-term follow-up. Some patient characteristics and tumor features were underrepresented in the randomized controlled trials, making it difficult to fully define IBR risks for patients with these features. Appropriate dose-fractionation regimens, target volume delineation, and treatment planning parameters for delivery of PBI are outlined. Intraoperative radiation therapy alone is associated with a higher IBR rate compared with WBI. A daily or every-other-day external beam PBI regimen is preferred over twice-daily regimens due to late toxicity concerns. CONCLUSIONS: Based on published data, the ASTRO task force has proposed recommendations to inform best clinical practices on the use of PBI.

Tumor Intrinsic Subtypes and Gene Expression Signatures in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Pooled Analysis of CALGB 40601, NeoALTTO, and NSABP B-41 Trials.

Importance: Biologic features may affect pathologic complete response (pCR) and event-free survival (EFS) after neoadjuvant chemotherapy plus ERBB2/HER2 blockade in ERBB2/HER2-positive early breast cancer (EBC). Objective: To define the quantitative association between pCR and EFS by intrinsic subtype and by other gene expression signatures in a pooled analysis of 3 phase 3 trials: CALGB 40601, NeoALTTO, and NSABP B-41. Design, Setting, and Participants: In this retrospective pooled analysis, 1289 patients with EBC received chemotherapy plus either trastuzumab, lapatinib, or the combination, with a combined median follow-up of 5.5 years. Gene expression profiling by RNA sequencing was obtained from 758 samples, and intrinsic subtypes and 618 gene expression signatures were calculated. Data analyses were performed from June 1, 2020, to January 1, 2023. Main Outcomes and Measures: The association of clinical variables and gene expression biomarkers with pCR and EFS were studied by logistic regression and Cox analyses. Results: In the pooled analysis, of 758 women, median age was 49 years, 12% were Asian, 6% Black, and 75% were White. Overall, pCR results were associated with EFS in the ERBB2-enriched (hazard ratio [HR], 0.45; 95% CI, 0.29-0.70; P < .001) and basal-like (HR, 0.19; 95% CI, 0.04-0.86; P = .03) subtypes but not in luminal A or B tumors. Dual trastuzumab plus lapatinib blockade over trastuzumab alone had a trend toward EFS benefit in the intention-to-treat population; however, in the ERBB2-enriched subtype there was a significant and independent EFS benefit of trastuzumab plus lapatinib vs trastuzumab alone (HR, 0.47; 95% CI, 0.27-0.83; P = .009). Overall, 275 of 618 gene expression signatures (44.5%) were significantly associated with pCR and 9 of 618 (1.5%) with EFS. The ERBB2/HER2 amplicon and multiple immune signatures were significantly associated with pCR. Luminal-related signatures were associated with lower pCR rates but better EFS, especially among patients with residual disease and independent of hormone receptor status. There was significant adjusted HR for pCR ranging from 0.45 to 0.81 (higher pCR) and 1.21-1.94 (lower pCR rate); significant adjusted HR for EFS ranged from 0.71 to 0.94. Conclusions and relevance: In patients with ERBB2/HER2-positive EBC, the association between pCR and EFS differed by tumor intrinsic subtype, and the benefit of dual ERBB2/HER2 blockade was limited to ERBB2-enriched tumors. Immune-activated signatures were concordantly associated with higher pCR rates and better EFS, whereas luminal signatures were associated with lower pCR rates.

Quantitative proteomic mass spectrometry of protein kinases to determine dynamic heterogeneity of the human kinome.

The kinome is a dynamic system of kinases regulating signaling networks in cells and dysfunction of protein kinases contributes to many diseases. Regulation of the protein expression of kinases alters cellular responses to environmental changes and perturbations. We configured a library of 672 proteotypic peptides to quantify >300 kinases in a single LC-MS experiment using ten micrograms protein from human tissues including biopsies. This enables absolute quantitation of kinase protein abundance at attomole-femtomole expression levels, requiring no kinase enrichment and less than ten micrograms of starting protein from flash-frozen and formalin fixed paraffin embedded tissues. Breast cancer biopsies, organoids, and cell lines were analyzed using the SureQuant method, demonstrating the heterogeneity of kinase protein expression across and within breast cancer clinical subtypes. Kinome quantitation was coupled with nanoscale phosphoproteomics, providing a feasible method for novel clinical diagnosis and understanding of patient kinome responses to treatment.

Association of PIK3CA Mutation With Pathologic Complete Response and Outcome by Hormone Receptor Status and Intrinsic Subtype in Early-Stage ERBB2/HER2-Positive Breast Cancer.

Importance: PIK3CA mutations may be associated with outcomes of patients with ERBB2/HER2-positive early breast cancer (EBC). Objectives: To assess if PIK3CA mutations among patients with ERBB2/HER2-positive EBC are associated with treatment response and outcome, and if these associations vary by hormone receptor (HR) status or intrinsic molecular subtype (IMS). Design, Setting, and Participants: This cohort study derived data on 184 patients from the phase 3 neoadjuvant Cancer and Leukemia Group B (CALGB) 40601 trial that enrolled patients with ERBB2/HER2-positive EBC in North America between January 1, 2008, and December 31, 2012. Participants received neoadjuvant paclitaxel with trastuzumab, lapatinib, or both. Statistical analysis was performed from March 23, 2022, to March 9, 2023. Exposures: Gene expression profiling by RNA sequencing with Prediction Analysis of Microarray 50-determined IMS and PIK3CA mutations from whole-exome sequencing were obtained from pretreatment biopsies from 184 of 305 trial participants. Main Outcomes and Measures: The primary end point was pathologic complete response (pCR) and the secondary end point of event-free survival (EFS). The association of PIK3CA mutations with pCR and EFS by HR status and IMS was estimated using logistic and Cox proportional hazards regression models. Results: All 184 participants were women, with a median age of 49 years (range 24-75 years). A total of 121 participants (66%) had clinical stage II tumors; 32 (17%) had PIK3CA mutations, most frequently H1047R (38% [12 of 32]) and E545K (22% [7 of 32]). PIK3CA mutations were present in 20 of 102 cases of HR-positive EBC (20%) and 12 of 82 cases HR-negative EBC (15%) and varied by IMS (luminal B, 9 of 25 [36%]; luminal A, 2 of 21 [10%]; and ERBB2/HER2-enriched tumors, 19 of 102 [19%]). Pathologic complete response rates were lower in PIK3CA mutated than PIK3CA wild type in the overall population (34% [11 of 32] vs 49% [74 of 152]; P = .14) and were significantly different among those receiving trastuzumab (30% [7 of 23] vs 54% [63 of 117]; P = .045). At a median follow-up of 9 years, PIK3CA mutations were significantly associated with worse EFS in the overall cohort (hazard ratio, 2.58 [95% CI, 1.24-5.35]; P = .01), which persisted in a multivariable model including pCR, HR status, stage, and IMS (hazard ratio, 2.52 [95% CI, 1.16-5.47]; P = .02). The negative association of PIK3CA mutation was significant in HR-positive (hazard ratio, 3.60 [95% CI, 1.45-8.96]; P = .006) and luminal subtypes (hazard ratio, 4.84 [95% CI, 1.08-21.70]; P = .04), but not in nonluminal and HR-negative tumors. Conclusions and Relevance: In ERBB2/HER2-positive EBC, PIK3CA mutations were associated with lower pCR rates and independently associated with worse long-term EFS. These findings appear to be associated with PIK3CA mutations in HR-positive and luminal EBC.

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer.

PURPOSE.­: To update the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. An Update Panel is aware that a new generation of antibody-drug conjugates targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification. METHODS.­: The Update Panel conducted a systematic literature review to identify signals for updating recommendations. RESULTS.­: The search identified 173 abstracts. Of 5 potential publications reviewed, none constituted a signal for revising existing recommendations. RECOMMENDATIONS.­: The 2018 ASCO-CAP recommendations for HER2 testing are affirmed. DISCUSSION.­: HER2 testing guidelines have focused on identifying HER2 protein overexpression or gene amplification in breast cancer to identify patients for therapies that disrupt HER2 signaling. This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is immunohistochemistry (IHC) 1+ or 2+ without amplification by in situ hybridization. Clinical trial data on tumors that tested IHC 0 are limited (excluded from DESTINY-Breast04), and evidence is lacking that these cancers behave differently or do not respond similarly to newer HER2 antibody-drug conjugates. Although current data do not support a new IHC 0 versus 1+ prognostic or predictive threshold for response to trastuzumab deruxtecan, this threshold is now relevant because of the trial entry criteria that supported its new regulatory approval. Therefore, although it is premature to create new result categories of HER2 expression (eg, HER2-Low, HER2-Ultra-Low), best practices to distinguish IHC 0 from 1+ are now clinically relevant. This update affirms prior HER2 reporting recommendations and offers a new HER2 testing reporting comment to highlight the current relevance of IHC 0 versus 1+ results and best practice recommendations to distinguish these often subtle differences. Additional information is available at www.asco.org/breast-cancer-guidelines.

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-College of American Pathologists Guideline Update.

PURPOSE: To update ASCO-College of American Pathologists (CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. The Panel is aware that a new generation of antibody-drug conjugates (ADCs) targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification. METHODS: An Update Panel conducted a systematic literature review to identify signals for updating recommendations. RESULTS: The search identified 173 abstracts. Of five potential publications reviewed, none constituted a signal for revising existing recommendations. RECOMMENDATIONS: The 2018 ASCO-CAP recommendations for HER2 testing are affirmed. DISCUSSION: HER2 testing guidelines have focused on identifying HER2 protein overexpression or gene amplification in breast cancer to identify patients for therapies that disrupt HER2 signaling. This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is immunohistochemistry (IHC) 1+ or 2+ without amplification by in situ hybridization. Clinical trial data on tumors that tested IHC 0 are limited (excluded from DESTINY-Breast04), and evidence is lacking that these cancers behave differently or do not respond similarly to newer HER2 ADCs. Although current data do not support a new IHC 0 versus 1+ prognostic or predictive threshold for response to trastuzumab deruxtecan, this threshold is now relevant because of the trial entry criteria that supported its new regulatory approval. Therefore, while it is premature to create new result categories of HER2 expression (eg, HER2-Low, HER2-Ultra-Low), best practices to distinguish IHC 0 from 1+ are now clinically relevant. This Update affirms prior HER2 reporting recommendations and offers a new HER2 testing reporting comment to highlight the current relevance of IHC 0 versus 1+ results and best practice recommendations to distinguish these often subtle differences.Additional information is available at www.asco.org/breast-cancer-guidelines.

Prognostic and Predictive Value of Immune-Related Gene Expression Signatures vs Tumor-Infiltrating Lymphocytes in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Correlative Analysis of the CALGB 40601 and PAMELA Trials.

Importance: Both tumor-infiltrating lymphocytes (TILs) assessment and immune-related gene expression signatures by RNA profiling predict higher pathologic complete response (pCR) and improved event-free survival (EFS) in patients with early-stage ERBB2/HER2-positive breast cancer. However, whether these 2 measures of immune activation provide similar or additive prognostic value is not known. Objective: To examine the prognostic ability of TILs and immune-related gene expression signatures, alone and in combination, to predict pCR and EFS in patients with early-stage ERBB2/HER2-positive breast cancer treated in 2 clinical trials. Design, Setting, and Participants: In this prognostic study, a correlative analysis was performed on the Cancer and Leukemia Group B (CALGB) 40601 trial and the PAMELA trial. In the CALGB 40601 trial, 305 patients were randomly assigned to weekly paclitaxel with trastuzumab, lapatinib, or both for 16 weeks. The primary end point was pCR, with a secondary end point of EFS. In the PAMELA trial, 151 patients received neoadjuvant treatment with trastuzumab and lapatinib for 18 weeks. The primary end point was the ability of the HER2-enriched subtype to predict pCR. The studies were conducted from October 2013 to November 2015 (PAMELA) and from December 2008 to February 2012 (CALGB 40601). Data analyses were performed from June 1, 2020, to January 1, 2022. Main Outcomes and Measures: Immune-related gene expression profiling by RNA sequencing and TILs were assessed on 230 CALGB 40601 trial pretreatment tumors and 138 PAMELA trial pretreatment tumors. The association of these biomarkers with pCR (CALGB 40601 and PAMELA) and EFS (CALGB 40601) was studied by logistic regression and Cox analyses. Results: The median age of the patients was 50 years (IQR, 42-50 years), and 305 (100%) were women. Of 202 immune signatures tested, 166 (82.2%) were significantly correlated with TILs. In both trials combined, TILs were significantly associated with pCR (odds ratio, 1.01; 95% CI, 1.01-1.02; P = .02). In addition to TILs, 36 immune signatures were significantly associated with higher pCR rates. Seven of these signatures outperformed TILs for predicting pCR, 6 of which were B-cell related. In a multivariable Cox model adjusted for clinicopathologic factors, including PAM50 intrinsic tumor subtype, the immunoglobulin G signature, but not TILs, was independently associated with EFS (immunoglobulin G signature-adjusted hazard ratio, 0.63; 95% CI, 0.42-0.93; P = .02; TIL-adjusted hazard ratio, 1.00; 95% CI, 0.98-1.02; P = .99). Conclusions and Relevance: Results of this study suggest that multiple B-cell-related signatures were more strongly associated with pCR and EFS than TILs, which largely represent T cells. When both TILs and gene expression are available, the prognostic value of immune-related signatures appears to be superior.

Financial Toxicity Monitoring in a Randomized Controlled Trial of Patient-Reported Outcomes During Cancer Treatment (Alliance AFT-39).

PURPOSE: Financial toxicity (FT) affects 20% of cancer survivors and is associated with poor clinical outcomes. No large-scale programs have been implemented to mitigate FT. We evaluated the effect of monthly FT screening as part of a larger patient-reported outcomes (PROs) digital monitoring intervention. METHODS: PRO-TECT (AFT-39) is a cluster-randomized trial of patients undergoing systemic therapy for metastatic cancer. Practices were randomly assigned 1:1 to digital symptom monitoring (PRO practices) or usual care (control practices). Digital monitoring consisted of between-visit online or automated telephone patient surveys about symptoms, functioning, and FT (single-item screening question from Functional Assessment of Chronic Illness Therapy-COmprehensive Score for financial Toxicity) for up to 1 year, with automated alerts sent to practice nurses for concerning survey scores. Clinical team actions in response to alerts were not mandated. The primary outcome of this planned secondary analysis was development or worsening of financial difficulties, assessed via the European Organisation for Research and Treatment of Cancer QLQ-C30 financial difficulties measure, at any time compared with baseline. A randomly selected subset of patients and nurses were interviewed about their experiences with the intervention. RESULTS: One thousand one hundred ninety-one patients were enrolled (593 PRO; 598 control) at 52 US community oncology practices. Overall, 30.2% of patients treated at practices that received the FT screening intervention developed, or experienced worsening of, financial difficulties, compared with 39.0% treated at control practices (P = .004). Patients and nurses interviewed stated that FT screening identified patients for financial counseling who otherwise would be reluctant to seek, or unaware of the availability of, assistance. CONCLUSION: In this report of a secondary outcome from a randomized clinical trial, FT screening as part of routine digital patient monitoring with PROs reduced the development, or worsening, of financial difficulties among patients undergoing systemic cancer therapy.

The emerging role of real-world data in advanced breast cancer therapy: Recommendations for collaborative decision-making.

Among stakeholders and decision-makers in advanced breast cancer, the demand for insights from real-world data (RWD) is increasing. Although RWD can be used to support decisions throughout different stages of a breast cancer drug's life cycle, barriers exist to its use and acceptance. We propose a collaborative approach to generating and using RWD that is meaningful to multiple stakeholders, and encourage frameworks toward international guidelines to help standardize RWD methodologies to achieve more efficient use of RWD insights.

The Breast Cancer Weight Loss trial (Alliance A011401): A description and evidence for the lifestyle intervention.

The Breast Cancer Weight Loss (BWEL) trial is a randomized controlled trial designed to determine whether weight loss after a breast cancer diagnosis can reduce the risk of cancer recurrence in women with overweight or obesity. The BWEL trial will compare the efficacy of a telephone-based weight-loss intervention plus health education materials versus health education materials alone on invasive disease-free survival in 3,181 women with stage II or III breast cancer and BMI > 27 kg/m2 . This report provides a detailed description of the goals and methods of the lifestyle intervention and the evidence supporting the intervention used in the BWEL trial. The intervention's primary goal for participants is to achieve and maintain a weight loss ≥ 10% of baseline weight through increased physical activity and caloric restriction. The evidence supporting the diet, physical activity, and behavioral components of this telephone-based weight-loss intervention, as well as strategies to promote participant engagement and retention, is described. The intervention is provided through 42 sessions delivered by trained health coaches over a 2-year period. If the BWEL lifestyle intervention is successful in improving cancer outcomes, then weight loss will be incorporated into the care of thousands of breast cancer patients.

Surveillance Imaging vs Symptomatic Recurrence Detection and Survival in Stage II-III Breast Cancer (AFT-01).

BACKGROUND: Guidelines for follow-up after locoregional breast cancer treatment recommend imaging for distant metastases only in the presence of patient signs and/or symptoms. However, guidelines have not been updated to reflect advances in imaging, systemic therapy, or the understanding of biological subtype. We assessed the association between mode of distant recurrence detection and survival. METHODS: In this observational study, a stage-stratified random sample of women with stage II-III breast cancer in 2006-2007 and followed through 2016 was selected, including up to 10 women from each of 1217 Commission on Cancer facilities (n = 10 076). The explanatory variable was mode of recurrence detection (asymptomatic imaging vs signs and/or symptoms). The outcome was time from initial cancer diagnosis to death. Registrars abstracted scan type, intent (cancer-related vs not, asymptomatic surveillance vs not), and recurrence. Data were merged with each patient's National Cancer Database record. RESULTS: Surveillance imaging detected 23.3% (284 of 1220) of distant recurrences (76.7%, 936 of 1220 by signs and/or symptoms). Based on propensity-weighted multivariable Cox proportional hazards models, patients with asymptomatic imaging compared with sign and/or symptom detected recurrences had a lower risk of death if estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 negative (triple negative; hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.54 to 0.99), or HER2 positive (HR = 0.51, 95% CI = 0.33 to 0.80). No association was observed for ER- or PR-positive, HER2-negative (HR = 1.14, 95% CI = 0.91 to 1.44) cancers. CONCLUSIONS: Recurrence detection by asymptomatic imaging compared with signs and/or symptoms was associated with lower risk of death for triple-negative and HER2-positive, but not ER- or PR-positive, HER2-negative cancers. A randomized trial is warranted to evaluate imaging surveillance for metastases results in these subgroups.

CALGB 40603 (Alliance): Long-Term Outcomes and Genomic Correlates of Response and Survival After Neoadjuvant Chemotherapy With or Without Carboplatin and Bevacizumab in Triple-Negative Breast Cancer.

PURPOSE: CALGB 40603 (NCT00861705), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points. PATIENTS AND METHODS: The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing. RESULTS: Among baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P < .0001) and overall survival (87.9% v 63.4%, P < .0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS. CONCLUSION: Despite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival.