Ductal carcinoma in situ and cause-specific mortality among younger and older postmenopausal women: the Women's Health Initiative.

BACKGROUND: Whether DCIS is associated with higher breast cancer-specific and all-cause mortality is unclear with few studies in older women. Therefore, we examined DCIS and breast cancer-specific, cardiovascular (CVD)-specific, and all-cause mortality among Women's Health Initiative (WHI) Clinical Trial participants overall and by age (< 70 versus ≥ 70 years). METHODS: Of 68,132 WHI participants, included were 781 postmenopausal women with incident DCIS and 781 matched controls. Serial screening mammography was mandated with high adherence. DCIS cases were confirmed by central medical record review. Adjusted multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Kaplan Meier (KM) plots were used to assess 10-year and 20-year mortality rates. RESULTS: After 20.3 years total, and 13.2 years median post-diagnosis follow-up, compared to controls, DCIS was associated with higher breast cancer-specific mortality (HR 3.29; CI = 1.32-8.22, P = 0.01). The absolute difference in 20-year breast cancer mortality was 1.2% without DCIS and 3.4% after DCIS, log-rank P = 0.026. Findings were similar by age (< 70 versus ≥ 70 years) with no interaction (P interaction = 0.80). Incident DCIS was not associated with CVD-specific mortality (HR 0.77; CI-0.54-1.09, P = 0.14) or with all-cause mortality (HR 0.96; CI = 0.80-1.16, P = 0.68) with similar findings by age. CONCLUSIONS: In postmenopausal women, incident DCIS was associated with over three-fold higher breast cancer-specific mortality, with similar findings in younger and older postmenopausal women. These finding suggest caution in using age to adjust DCIS clinical management or research strategies.

Breast cancer incidence and mortality by metabolic syndrome and obesity: The Women's Health Initiative.

BACKGROUND: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials. METHODS: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status. RESULTS: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p = .03), 53% more deaths after breast cancer (p < .001), and 44% higher breast cancer mortality (p = .03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p < .001), more total breast cancers (p < .001), and more deaths after breast cancer (p < .001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m2; p < .001). CONCLUSIONS: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies.

Outcome prioritization and preferences among older adults with cancer starting chemotherapy in a randomized clinical trial.

INTRODUCTION: Older adults with cancer facing competing treatments must prioritize between various outcomes. This study assessed health outcome prioritization among older adults with cancer starting chemotherapy. METHODS: Secondary analysis of a randomized trial addressing vulnerabilities in older adults with cancer. Patients completed three validated outcome prioritization tools: 1) Health Outcomes Tool: prioritizes outcomes (survival, independence, symptoms) using a visual analog scale; 2) Now vs. Later Tool: rates the importance of quality of life at three times-today versus 1 or 5 years in the future; and 3) Attitude Scale: rates agreement with outcome-related statements. The authors measured the proportion of patients prioritizing various outcomes and evaluated their characteristics. RESULTS: A total of 219 patients (median [range] age 71 [65-88], 68% with metastatic disease) were included. On the Health Outcomes Tool, 60.7% prioritized survival over other outcomes. Having localized disease was associated with choosing survival as top priority. On the Now vs. Later Tool, 50% gave equal importance to current versus future quality of life. On the Attitude Scale, 53.4% disagreed with the statement "the most important thing to me is living as long as I can, no matter what my quality of life is"; and 82.2% agreed with the statement "it is more important to me to maintain my thinking ability than to live as long as possible". CONCLUSION: Although survival was the top priority for most participants, some older individuals with cancer prioritize other outcomes, such as cognition and function. Clinicians should elicit patient-defined priorities and include them in decision-making.

Impact of neoadjuvant pembrolizumab adherence on pathologic complete response in triple-negative breast cancer: a real-world analysis.

BACKGROUND: The addition of pembrolizumab (pembro) to neoadjuvant chemotherapy (NAC) is standard of care for the treatment of early triple-negative breast cancer (TNBC) after KEYNOTE-522 trial demonstrated improved pathologic complete response (pCR) rates with the combination. However, the optimal treatment strategy for TNBC remains uncertain as questions persist about which patients benefit from pembro and the best treatment schedule and regimen. We identified real-world clinical characteristics and treatment variables associated with response to NAC plus pembro. METHODS: Patients with early TNBC treated with NAC plus pembro between February 2020 and September 2023 were identified. Univariate and multivariate analysis was performed using logistic regression to identify factors associated with pCR. Cox proportional hazard prediction models were used to identify predictors of invasive disease-free survival and overall survival in this cohort. RESULTS: A pCR was achieved in 75 (63.6%) of 118 patients. Age at diagnosis (P = .04), Ki-67 (P = .004), duration from start of pembro to surgery (P = .006) and NAC to surgery (P = .01), number of cycles of pembro (P = .04) and NAC (P = .02), and completion of at least 8 cycles of pembro (P = .015) and NAC (P = .015) were each significantly associated with pCR in univariate analysis. In multivariate analysis, patients younger than 55 years at time of diagnosis (vs age > 55 years) and those completing at least 8 cycles of pembro remained predictive of pCR (OR's 2.50, 2.49, P = .035 and .037, respectively). CONCLUSIONS: In this real-world analysis of patients with TNBC treated with NAC plus pembro, younger age and the completion of at least 8 cycles of pembrolizumab were associated with pCR.

Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis.

PURPOSE: In the Women's Health initiative (WHI) randomized clinical trial, conjugated equine estrogen (CEE)-alone significantly reduced breast cancer incidence (P = 0.005). As cohort studies had opposite findings, other randomized clinical trials were identified to conduct a meta-analysis of estrogen-alone influence on breast cancer incidence. METHODS: We conducted literature searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analysis and reviews. In the meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, the corresponding log-RR = (O - E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP. RESULTS: Findings from 10 randomized trials included 14,282 participants and 591 incident breast cancers. In 9 smaller trials, with 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. Combining the 10 trials, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo (overall RR 0.77 95% CI 0.65-0.91, P = 0.002). CONCLUSION: The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence.

Association Between 18F-FDG PET Activity and HER2 Status in Breast Cancer Brain Metastases.

Purpose: The objective of this study was to evaluate whether uptake on 18F-fluorodeoxyglucose (18F-FDG) PET could help differentiate HER2-positive from HER2-negative breast cancer brain metastases. Methods: In this retrospective, cross-sectional study of a cohort of 14 histologically proven breast cancer brain metastases, we analyzed both preoperative 18F-FDG PET/CT and HER2 status of the resected/biopsied brain specimens. The maximum standardized uptake values (SUVmax) of the lesions were normalized to contralateral normal white matter and compared using Mann-Whitney U tests. Results: The study cohort was comprised of 12 women with breast cancer with a mean age of 59 years (range: 43-76 years) with a total of 14 distinct brain metastatic lesions. The SUVmax ratio of HER2-positive breast cancer brain metastases was significantly greater than that of HER2-negative lesions (3.98 vs 1.79, U = 38.00, p = 0.008). Conclusion: The SUVmax ratio may help to identify the HER2 status of breast cancer brain metastases, if validated prospectively.

A phase I study of Mirvetuximab Soravtansine and gemcitabine in patients with FRα-positive recurrent ovarian, primary peritoneal, fallopian tube, or endometrial cancer, or triple negative breast cancer.

OBJECTIVE: Platinum-resistant epithelial ovarian cancer (EOC), recurrent endometrial cancer (EC), and triple negative breast cancer (TNBC) are difficult to treat after failing standard therapies. This phase I study evaluated mirvetuximab soravtansine (MIRV) and gemcitabine in patients with recurrent FRα-positive EOC, EC, or TNBC to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) (primary endpoint). METHODS: FRα-positive patients with platinum-resistant EOC, EC, or TNBC with ≤4 prior chemotherapy regimens (2 for EC) were enrolled. FRα expression requirement varied among eligible tumors and changed during the study. RESULTS: Twenty patients were enrolled; 17 were evaluable for DLT. Half the patients received ≥3 prior chemotherapy lines. Most EOC and EC patients (78%) were medium (50-74%) or high(75-100%) FRα expressors. TNBC patients were low (25-49%) FRα expressors. The MTD/RP2D was MIRV 6 mg/kg AIBW D1 and gemcitabine 800 mg/m2 IV, D1 and D8, every 21 days (Dose Level [DL] 3), where 5/7 patients demonstrated a partial response (PR) as their best response, including 2 confirmed ovarian responses whose time-to-progression and duration of response were 7.9/5.4 and 8.0/5.7 months respectively. Most common treatment-related adverse events at MTD were anemia and neutropenia (3/7 each, 43%), diarrhea, hypophosphatemia, thrombocytopenia, and leukopenia (2/7 each, 29%). DLTs were thrombocytopenia (DL1), oral mucositis (DL4) and diarrhea (DL4). Nine of 20 patients (45%; 95% CI: 21.1-68.9%) achieved PR as their best response, with 3/20 patients or 15% (95%CI, 0-32.1%) confirmed PR. CONCLUSION: MIRV and gemcitabine demonstrate promising activity in platinum resistant EOC at RP2D, but frequent hematologic toxicities.

Pilot study of HER2 targeted 64 Cu-DOTA-tagged PET imaging in gastric cancer patients.

OBJECTIVE: Human epidermal growth factor receptor 2 (HER2) is an important biomarker for targeted gastric cancer (GC) immunotherapy. However, heterogeneous HER2 overexpression in GC, loss of HER2 expression during therapy, and inability to non-invasively identify HER2 overexpressing tumors impede effective targeting therapies. Improved HER2-specific functional imaging can address these challenges. Trastuzumab is a HER2-directed mAb to treat HER2 overexpressing cancers. The 64 Cu-DOTA-trastuzumab radiotracer is used to detect HER2+ metastatic breast cancer. We aimed to develop 64 Cu-DOTA-trastuzumab PET-CT to detect and characterize tumor uptake in HER2+ or - GC patients. METHODS: We conducted a single-arm phase II pilot study exploring the feasibility of 64 Cu-DOTA-trastuzumab for PET imaging of HER2 overexpressing GC compared to HER2 non-expressing tumors. Eight patients with biopsy-confirmed gastric adenocarcinoma were included. Immunohistochemistry was used to evaluate primary tumor biopsies for HER2 overexpression. Patients were injected with 45 mg of cold trastuzumab followed by 5 mg of 64 Cu-DOTA-trastuzumab. PET-CT scans were performed 24-48 h post radiotracer injection and compared to standard staging CT scans. RESULTS: We observed limited toxicity following 64 Cu-DOTA-trastuzumab injections. While there was uptake of the radiotracer in portions of HER2+ lesions, there was no statistically significant distinction between tumor and background by standardized uptake value analysis. CONCLUSION: Despite the potential of 64 Cu-DOTA-trastuzumab PET imaging of HER2+ metastatic breast cancer, a 5 mg dose of this radiotracer injected 24-48 h before imaging was insufficient to identify HER2+ GC. These results inform future GC imaging studies to optimize biomarker-targeted therapies based on dosage and timing for more clinically relevant imaging.

Bilateral Oophorectomy and Colorectal Cancer Incidence and Mortality in the Women's Health Initiative.

BACKGROUND: The few cohort studies examining oophorectomy and colorectal cancer risk provide mixed results. Therefore, we examined this issue in Women's Health Initiative Observational Study participants. METHODS: A total of 71,312 postmenopausal women were followed for 22.1 years (median). At enrollment, 55,643 (78%) had intact ovaries and 15,669 (22%) had undergone a bilateral oophorectomy. Colorectal cancers were verified by central medical record review with mortality findings enhanced by National Death Index queries. RESULTS: With 1,421 incident colorectal cancers, 450 colorectal cancer-specific mortalities, after controlling for covariates, bilateral oophorectomy was not associated with colorectal cancer incidence or colorectal cancer mortality. CONCLUSIONS: No significant associations between oophorectomy and colorectal cancer incidence and mortality were seen in a large cohort study with long follow-up. IMPACT: As the oophorectomy and colorectal cancer question remains open, further studies of high quality, even with null findings, should be encouraged.

Inflammation-related proteins as biomarkers of treatment-related behavioral symptoms: A longitudinal study of breast cancer patients and age-matched controls.

Background: Behavioral symptoms in breast cancer (BC) survivors have been attributed to cancer treatment and resulting inflammation. However, studies linking behavioral symptoms to BC treatment have observed patients only after some treatment. Our prospective study with pre-treatment baseline investigates post-treatment changes in inflammation-related biomarkers and whether those changes correlate with changes in symptoms. Methods: Participants were postmenopausal women, newly-diagnosed with stage 0-3 BC before any treatment (n = 173 "patients"), and age-matched women without cancer (n = 77 "controls"), who were assessed on plasma markers [soluble tumor necrosis factor receptor type 2 (sTNF-RII), interleukin (IL)-6, IL-1 receptor antagonist (IL-1RA), C-reactive protein (CRP)]) and symptoms (Physical Functioning, Pain, Attention/concentration, Perceived Cognitive Problems, Fatigue, Sleep Insufficiency, Depression). Participants were assessed again 1 month, 1 year, and 2 years after completing primary treatment or similar interval in controls. Generalized linear mixed models tested 4 treatments (surgery alone or with chemotherapy, radiation, or both) for association with change per marker. Joint models tested change per marker for association with change per symptom. Models considered demographic, socioeconomic, and clinical covariates. False Discovery Rate method controlled risk of error from multiple hypotheses. Results: At one month post-completion of treatment, sTNF-RII and IL-6 were elevated by all BC treatments, as were IL-1RA and CRP after surgery alone (all, p < 0.05). By 1 year, markers' average values returned to baseline. Throughout 2-year follow-up, increase-from-baseline in sTNF-RII, IL-1RA, and IL-6 coincided with worsened Physical Functioning, and increase-from-baseline in sTNF-RII coincided with increased Pain (all, p < 0.01). These biomarker-symptom associations (excepting IL-6) were exclusive to patients. No other symptoms worsened, and baseline Fatigue and Depression improved in all participants. Conclusions: BC treatment, even surgery, is associated with transient elevation in inflammatory markers. In patients post-treatment, increase-from-baseline in sTNF-RII accompanies increased Pain and decreased Physical Functioning, suggesting that sTNF-RII merits development as a clinical biomarker in BC patients.

HER2-targeted antibody-drug conjugates for breast cancer: ancestry and dose adjustment for thrombocytopenia.

BACKGROUND: Thrombocytopenia is a common adverse event on HER2-targeted therapies, fam-trastuzumab deruxtecan (T-DXd) and ado-trastuzumab emtansine (T-DM1). A reported association of Asian ancestry with this event merits investigation to rule out potential confounding. METHODS: Subjects in this retrospective cohort were female patients with HER2 positive breast cancer, of Asian or non-Hispanic White ancestry, who initiated T-DM1 or T-DXd from January 2017 through October 2021. Follow-up closed in January 2022. Primary endpoint was dose adjustment for thrombocytopenia. Competing endpoints were discontinuation of drug for other toxicity, disease progression, or for completion of prescribed cycles. The association between Asian ancestry and thrombocytopenia-related dose adjustment was tested at p < 0.01 in a proportional hazards model for the sub-distributions of 4 (primary and competing) endpoints. Covariates examined as potential confounders were age, metastatic disease, specific HER2-targeted drug, and prior drug switching for toxicity. RESULTS: Among 181 subjects, 48 reported Asian ancestry. Incidence of dose adjustment for thrombocytopenia was higher in patients with Asian ancestry and among patients switched to T-DXd after experiencing thrombocytopenia on T-DM1. Independent of specific drug and prior drug switching, Asian ancestry was associated with dose adjustment for thrombocytopenia (hazards ratio 2.95, 95% confidence interval 1.41-6.18) but not with competing endpoints. Among participants of Asian ancestry, the ancestral origin was usually China or the Philippines (where Chinese ancestry is common). CONCLUSIONS: The association between Asian ancestry and thrombocytopenia on HER2-targeted therapy is independent of age, metastatic disease, drug, and history of similar toxicity. This association may have a genetic basis linked to Chinese ancestry.

Thrombopoietin Receptor Agonists for Thrombocytopenia Secondary to HER2-Targeted Antibody Drug Conjugates.

Trastuzumab emtansine and trastuzumab deruxtecan are widely used in breast cancer and other solid tumor malignancies. Thrombocytopenia is a common adverse event associated with the use of these agents that can lead to a treatment delay, reduction in dose intensity, and discontinuation. The role of thrombopoietin receptor agonists (TPO-RA) remains unknown in this setting. We report a case series of 6 individuals with breast cancer that experienced dose-reductions and therapy delays due to thrombocytopenia secondary to trastuzumab emtansine or trastuzumab deruxtecan therapy and received intervention with TPO-RA. All 6 were able to resume therapy with TPO-RA support.

NCCN Guidelines® Insights: Breast Cancer, Version 4.2023.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer address all aspects of management for breast cancer. The treatment landscape of metastatic breast cancer is evolving constantly. The therapeutic strategy takes into consideration tumor biology, biomarkers, and other clinical factors. Due to the growing number of treatment options, if one option fails, there is usually another line of therapy available, providing meaningful improvements in survival. This NCCN Guidelines Insights report focuses on recent updates specific to systemic therapy recommendations for patients with stage IV (M1) disease.

Predicting All-Cause Mortality in Women With and Without Breast Cancer Using the Schonberg Index: A Women's Health Initiative Study.

BACKGROUND: When treating older women with breast cancer, life expectancy is an important consideration. ASCO recommends calculating 10-year mortality probabilities to inform treatment decisions. One useful tool is the Schonberg index, which predicts risk-based all-cause 10-year mortality. We investigated the use of this index in women aged ≥65 years with breast cancer in the Women's Health Initiative (WHI). METHODS: We calculated 10-year mortality risk scores for 2,549 WHI participants with breast cancer ("cases") and 2,549 age-matched breast cancer-free participants ("controls") using Schonberg index risk scoring. Risk scores were grouped into quintiles for comparisons. Risk-stratified observed mortality rates and 95% confidence intervals were compared across cases and controls. Observed 10-year mortality rates in cases and controls were also compared with Schonberg index-based predicted 10-year mortality rates. RESULTS: Compared with controls, cases were more often white (P=.005), had higher income and education levels (P<.001 for both), more often lived with their husband/partner (P<.001), scored higher on subjective health/happiness (P<.001), and needed less assistance in activities of daily living (P<.001). Participants with breast cancer had similar risk-stratified 10-year mortality rates compared with controls (34% vs 33%, respectively). Stratified results showed that cases had slightly higher mortality rates than controls in the lowest risk quintile and lower mortality rates in the 2 highest risk quintiles. Observed mortality rates in cases and controls were similar to Schonberg index-predicted mortality, with model c-indexes of 0.71 and 0.76, respectively. CONCLUSIONS: Among women aged ≥65 years with incident breast cancer, the Schonberg index-based risk-stratified 10-year mortality rates were similar to those in women without breast cancer, demonstrating a similar performance of the index among both populations. Along with other health measures, prognostic indexes can help predict survival among older women with breast cancer and support geriatric oncology guidelines that promote using life expectancy calculation tools for shared decision-making.

The Challenges of Treating Patients with Breast Cancer and Obesity.

Obesity is defined as a body mass index (BMI) of 30 kg/m2 or more and is associated with worse outcomes in patients with breast cancer, resulting in an increased incidence of breast cancer, recurrence, and death. The incidence of obesity is increasing, with almost half of all individuals in the United States classified as obese. Patients with obesity present with unique pharmacokinetics and physiology and are at increased risk of developing diabetes mellitus and cardiovascular disease, which leads to specific challenges when treating these patients. The aim of this review is to summarize the impact of obesity on the efficacy and toxicity of systemic therapies used for breast cancer patients, describe the molecular mechanisms through which obesity can affect systemic therapies, outline the existing American Society of Clinical Oncology (ASCO) guidelines for treating patients with cancer and obesity, and highlight additional clinical considerations for treating patients with obesity and breast cancer. We conclude that further research on the biological mechanisms underlying the obesity-breast cancer link may offer new treatment strategies, and clinicals trials that focus on the treatment and outcomes of patients with obesity and all stages of breast cancer are needed to inform future treatment guidelines.

Summary: Appropriate Use Criteria for Estrogen Receptor-Targeted PET Imaging with 16α-18F-Fluoro-17ß-Fluoroestradiol.

PET imaging with 16α-18F-fluoro-17ß-fluoroestradiol (18F-FES), a radiolabeled form of estradiol, allows whole-body, noninvasive evaluation of estrogen receptor (ER). 18F-FES is approved by the U.S. Food and Drug Administration as a diagnostic agent "for the detection of ER-positive lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer." The Society of Nuclear Medicine and Molecular Imaging (SNMMI) convened an expert work group to comprehensively review the published literature for 18F-FES PET in patients with ER-positive breast cancer and to establish appropriate use criteria (AUC). The findings and discussions of the SNMMI 18F-FES work group, including example clinical scenarios, were published in full in 2022 and are available at https://www.snmmi.org/auc Of the clinical scenarios evaluated, the work group concluded that the most appropriate uses of 18F-FES PET are to assess ER functionality when endocrine therapy is considered either at initial diagnosis of metastatic breast cancer or after progression of disease on endocrine therapy, the ER status of lesions that are difficult or dangerous to biopsy, and the ER status of lesions when other tests are inconclusive. These AUC are intended to enable appropriate clinical use of 18F-FES PET, more efficient approval of FES use by payers, and promotion of investigation into areas requiring further research. This summary includes the rationale, methodology, and main findings of the work group and refers the reader to the complete AUC document.

Predicting Hyperglycemia Among Patients Receiving Alpelisib Plus Fulvestrant for Metastatic Breast Cancer.

BACKGROUND: Hyperglycemia is recognized as a common adverse event for patients receiving alpelisib but has been little studied outside of clinical trials. We report the frequency of alpelisib-associated hyperglycemia in a real-world setting and evaluate proposed risk factors. PATIENTS AND METHODS: We retrospectively identified patients with PIK3CA-mutated, hormone receptor-positive, metastatic breast cancer who initiated treatment with alpelisib plus fulvestrant between August 2019 and December 2021. Ordinal logistic regression evaluated 5 characteristics (diabetes, prediabetes, body mass index [BMI], age, and Asian ancestry) as independent risk factors for ALP-associated hyperglycemia grades 2-4. Risk of error from multiple hypothesis testing was controlled using the false discovery rate method. RESULTS: The study included n = 92 subjects, all but 1 female, mean age 59.9 (+11.9) years with 50% non-Hispanic White, 15% Hispanic/Latino, 13% Asian, 9% African/Black, and 13% other/unknown. In total 34% of patients had diabetes, 10% had pre-diabetes, and 56% had normoglycemia. Thirty-six percent were obese, 32% were overweight, 25% were normal weight, and 7% were lean. Frequency of grades 1-4 hyperglycemia in current subjects (64.1%) was similar to hyperglycemia reported in the SOLAR-1 trial (63.7%). Our subjects' risk of grades 2-4 hyperglycemia was independently increased by pre-existing diabetes (Odds ratio 3.75, 95% CI, 1.40-10.01), pre-diabetes (6.22, 1.12-34.47), Asian ancestry (7.10, 1.75-28.84), and each unit of BMI above 20 (1.17, 1.07-1.28). CONCLUSION: While receiving alpelisib, patients of Asian ancestry, as well as patients with pre-existing hyperglycemia and/or BMI above 20, should be closely monitored for hyperglycemia. The mechanism underlying the current association of alpelisib-associated hyperglycemia with Asian ancestry is independent of BMI and merits further study. The high incidence of hyperglycemia resulted in a change in practice to include consultation with a diabetes nurse educator or endocrinologist at the start of alpelisib.

Hyperglycemia and Glycemic Variability Associated with Glucocorticoids in Women without Pre-Existing Diabetes Undergoing Neoadjuvant or Adjuvant Taxane Chemotherapy for Early-Stage Breast Cancer.

Glucocorticoids, which are administered with chemotherapy, cause hyperglycemia. Glycemic variability among breast cancer patients without diabetes is not well known. A retrospective cohort study was conducted involving early-stage breast cancer patients without diabetes who received dexamethasone prior to neoadjuvant or adjuvant taxane chemotherapy between August 2017-December 2019. Random blood glucose levels were analyzed, and steroid-induced hyperglycemia (SIH) was defined as a random glucose level of >140 mg/dL. A multivariate proportional hazards model was used to identify the risk factors of SIH. Out of 100 patients, the median age was 53 years (IQR: 45-63.5). A total of 45% of patients were non-Hispanic White, 28% Hispanic, 19% Asian, and 5% African American. The incidence of SIH was 67%, and glycemic fluctuations were highest in those with glucose levels of >200 mg/dL. Non-Hispanic White patients represented a significant predictor for time to SIH, with a hazard ratio of 2.5 (95% CI: 1.04, 5.95, p = 0.039). SIH was transient in over 90% of the patients, and only seven patients remained hyperglycemic after glucocorticoid and chemotherapy completion. Pretaxane dexamethasone-induced hyperglycemia was observed in 67% of the patients, with the greatest glycemic lability in those patients with blood glucose levels of >200 mg/dL. The non-Hispanic White patients had a higher risk of developing SIH.

Phase 2 prospective open label study of neoadjuvant nab-paclitaxel, trastuzumab, and pertuzumab in patients with HER2-positive primary breast cancer.

BACKGROUND: The objective of this study was to evaluate the safety and efficacy of nab-paclitaxel, trastuzumab, and pertuzumab as neoadjuvant therapy (NAT) in patients with human epidermal growth factor receptor 2 HER2+ breast cancer (HER2+ BC) to determine pathologic complete response (pCR), invasive disease-free survival (iDFS), and overall survival. METHODS: Forty-five patients with HER2+ BC Stages II-III were to be enrolled from 2013 to 2017. Patients were treated with weekly nab-paclitaxel (100 mg/m2 intravenously), weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg), and six cycles of pertuzumab (840 mg loading dose, then 420 mg intravenously day 1 every 21 days). RESULTS: Median follow-up was 60 months (95% CI, 32.3-55.6) and pCR was 29/45 (64%). The 5-year iDFS for patients who achieved pCR (N = 29) was 96.3% (95% CI, 76.5-99.5) and non-pCR patients (N = 16) was 74.3% (95% CI, 39.1-91.0). The 5-year overall survival (N = 45) was 94.1% (95% CI, 77.6-98.5). Based on hormonal status, the 5-year iDFS for HR+ pCR patients (N = 14) was 92.3% (95% CI, 56.6-98.9) and for HR- (N = 15) was 100% (p = .3). CONCLUSIONS: This anthracycline/carboplatin-free regimen with nab-paclitaxel achieved a pCR rate of 64% in patients with HER2+ BC. The 5-year iDFS in patients with and without pCR was 96.3% and 74.3%, respectively. The pCR rate is comparable with docetaxel, carboplatin, trastuzumab, and pertuzumab therapy in the NAT setting, but with fewer treatment-associated toxicities. This finding suggests the possibility of safe avoidance of anthracyclines and carboplatin as components of NAT in patients with HER2+ BC.

Association of lesion contour and lesion composition on MR with HER2 status in breast cancer brain metastases.

BACKGROUND AND PURPOSE: With the development of HER2-directed therapies, identifying non-invasive imaging biomarkers of HER2 status in breast cancer brain metastases has become increasingly important, particularly given the risks of tissue sampling within the brain and the possibility of a change in receptor expression from the primary tumor to the brain metastasis. The purpose of this study was to evaluate whether lesion contour and composition on MR could help identify the HER2 status of breast cancer brain metastases. MATERIALS AND METHODS: We derived a cohort of 34 women with a mean age of 55 years (range: 31-81 years) with a total of 47 distinct histologically proven breast cancer brain metastases with preoperative contrast-enhanced brain MR and HER2 immunohistochemistry and/or fluorescent in-situ hybridization (FISH) of the resected/biopsied brain specimens from 2018 to 2021. Two fellowship-trained neuroradiologists evaluated the lesion contour and lesion composition of each lesion. Logistic regression analyses were performed. RESULTS: In a logistic regression model, an irregular contour had an odds ratio of 170 (p = 0.007) in differentiating HER2-positive from HER2-negative lesions. In a logistic regression model, when compared to a predominantly cystic lesion composition, a solid lesion composition had an odds ratio of 17 (p = 0.016) in differentiating HER2-positive from HER2-negative lesions. CONCLUSION: Lesion contour and lesion composition on MR were significantly associated with the HER2 status of breast cancer brain metastases. Current assessment of HER2 status requires tissue sampling and immunochemical and/or FISH analyses. A non-invasive imaging biomarker that may help predict HER2 status may be of great clinical value.