Cerebrospinal Fluid Testing in Leptomeningeal Progression of HER2-Negative Breast Cancer Reveals HER2 Positivity, Leading to HER2-Targeted Therapy: A Case Report.

The treatment of breast cancer is largely determined by protein expression assays of estrogen receptor, progesterone receptor, and Her2/neu (HER2) status. These prognostic markers may vary due to tumor heterogeneityor the evolution of prognostic markers throughout the course of treatment. This report presents a case of a patient who initially presented with HER2-negative breast cancer and had rapidly progressed on numerous lines of treatment. An analysis of cerebrospinal fluid via next-generation sequencing and biopsy of metastasis to the liver identified HER2-positive cancer, which allowed for the use of trastuzumab deruxtecan, a HER2-targeted therapy. This led to an excellent clinical response with improvement in performance status and quality of life. This case report demonstrates the importance of continuing to follow a patient's cancer pathology to open the doors for other opportunities for treatment. Cancer has the potential to evolve and there is a benefit of obtaining rebiopsies to ensure the correct targeted therapies are provided to the patient.

Avanzando Caminos (Leading Pathways): Design and Procedures of The Hispanic/Latino Cancer Survivorship Study.

PURPOSE: Avanzando Caminos (Leading Pathways): The Hispanic/Latino Cancer Survivorship Cohort Study aims to examine the influence of sociocultural, medical, stress, psychosocial, lifestyle, behavioral, and biological factors on symptom burden, health-related quality of life, and clinical outcomes among Hispanics/Latinos who have been previously treated for cancer. METHODS: Avanzando Caminos is a prospective, cohort-based study of 3,000 Hispanics/Latinos who completed primary cancer treatment within the past five years that is representative of the general Hispanic/Latino population in the U.S. Participants will complete self-report measures at baseline (T1), 6 months (T2), 1 year (T3), 2 years (T4), 3 years (T5), 4 years (T6), and 5 years (T7). Blood draws to assess leukocyte gene expression, cardiometabolic markers, and genetic admixture will be collected at baseline (T1), 1 year (T3), 3 years (T5), and 5 years (T7). Medical and cancer characteristics and clinical outcomes will be extracted from the electronic medical record and/or state cancer registry at each time point. Data analysis will include general latent variable modeling and latent growth modeling. CONCLUSIONS: Avanzando Caminos will fill critical gaps in knowledge to guide future secondary and tertiary prevention efforts to mitigate cancer disparities and optimize health-related quality of life among Hispanic/Latino cancer survivors.

Triple Primary Cancers: An Analysis of Genetic and Environmental Factors.

The occurrence of multiple primary cancers (MPC) is thought to reflect increased cancer susceptibility in patients due to a combination of genetic and environmental factors. Here we conducted a retrospective review of 2,894 consecutive patients evaluated at a single institution and identified 31 (1.14%) individuals with a history of three or more primary cancers, then analyzed the genetic and environmental influences associated with their propensity for developing malignancies. We found that 35.5% of patients had a hereditary cancer syndrome (HCS), with high penetrance HCS in 72.7% of cases, suggesting that monogenic causes underly a significant proportion of triple primary cancer risk. Analysis of cancer frequencies found that the diagnosis of breast cancer was associated with a significantly lower likelihood of HCS, while the diagnosis of colorectal, prostate, and pancreas cancer was associated with a significantly higher likelihood of HCS. Comparison of HCS-positive and HCS-negative patients revealed similar demographic characteristics, mean age at first diagnosis, and family history of cancer. Moreover, no significant differences in lifestyle behaviors, occupational exposures, chronic health conditions, or treatment with chemotherapy and radiation were observed between HCS-positive and -negative groups, though outliers in tobacco smoking, as well as systemic treatment after both first and second primary cancers were observed. These findings indicate a robust contribution of HCS to cancer susceptibility among patients with triple primary cancers while environmental influences were less evident. This emphasizes the need for larger MPC cohorts incorporating additional genetic and environmental factors to more comprehensively characterize drivers of cancer risk. PREVENTION RELEVANCE: In patients with three or more primary cancers, genetic predisposition explained a significant proportion of cases; however, treatment history, lifestyle habits, and other exposures appeared to play a less significant role. This highlights the value of early genetic screening and the need to develop more sensitive markers of cancer susceptibility. See related Spotlight, p. 193.

Sunitinib in Patients With Breast Cancer With FGFR1 or FGFR2 Amplifications or Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results from cohorts of patients with metastatic breast cancer (BC) with FGFR1 and FGFR2 alterations treated with sunitinib are reported. METHODS: Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16 weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Forty patients with BC with FGFR1 (N = 30; amplification only n = 26, mutation only n = 1, both n = 3) or FGFR2 (N = 10; amplification only n = 2, mutation only n = 6, both n = 2) alterations were enrolled. Three patients in the FGFR1 cohort were not evaluable for efficacy; all patients in the FGFR2 cohort were evaluable. For the FGFR1 cohort, two patients with partial response and four with SD16+ were observed for DC and OR rates of 27% (90% CI, 13 to 100) and 7% (95% CI, 1 to 24), respectively. The null hypothesis of 15% DC rate was not rejected (P = .169). No patients achieved DC in the FGFR2 cohort (P = 1.00). Thirteen of the 40 total patients across both cohorts had at least one grade 3-4 adverse event or serious adverse event at least possibly related to sunitinib. CONCLUSION: Sunitinib did not meet prespecified criteria to declare a signal of antitumor activity in patients with BC with either FGFR1 or FGFR2 alterations. Other treatments and clinical trials should be considered for these patient populations.

The Effect of Disability and Social Determinants of Health on Breast and Cervical Cancer Screenings During the COVID-19 Pandemic.

Introduction: The objective of this study was to examine the effect of disability status and social determinants of health (SDOH) on adherence to breast and cervical cancer screening recommendations during the COVID-19 pandemic. Methods: We conducted a secondary analysis of the 2018 and 2020 Behavioral Risk Factor Surveillance System (BRFSS) data sets. We defined adherence to screenings according to the US Preventive Services Task Force guidelines for breast and cervical cancer screening. The analysis included respondents assigned female at birth, aged 50 to 74 years (breast cancer screening) or aged 21 to 65 years (cervical cancer screening). We performed logistic regression to evaluate breast and cervical cancer screening adherence, by disability status and SDOH (health insurance coverage, marital status, and urban residency), independently and simultaneously. Results: Our analysis included 27,526 BRFSS respondents in 2018 and 2020. In 2018, women with disabilities had lower adjusted odds than women without disabilities of being up to date with mammograms (adjusted odds ratio [AOR] = 0.76, 95% CI, 0.63-0.93) and Pap (Papanicolaou) tests (AOR = 0.73; 95% CI, 0.59-0.89). In 2020, among women with disabilities, the adjusted odds of mammogram and Pap test adherence decreased (AOR = 0.69; 95% CI, 0.54-0.89; AOR = 0.59; 95% CI, 0.47-0.75, respectively). In 2018, the adjusted odds of mammogram adherence among rural residents with and without disabilities were 0.83 (95% CI, 0.70-0.98), which decreased to 0.76 (95% CI, 0.62-0.93) in 2020. Conclusion: The findings of this study highlight the effect of disability status and SDOH on breast and cervical cancer screening rates during the COVID-19 pandemic. Public health strategies that acknowledge and address these disparities are crucial in preparing for future public health crises.

Cobimetinib Plus Vemurafenib in Patients With Solid Tumors With BRAF Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. The results in a cohort of patients with solid tumors with BRAF mutations treated with cobimetinib plus vemurafenib are reported. METHODS: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as complete response (CR) or partial response (PR) or stable disease of at least 16-weeks duration (SD16+). Low-accruing histology-specific cohorts with BRAF mutations treated with cobimetinib plus vemurafenib were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power, .82; α, .10). The secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Thirty-one patients with solid tumors with BRAF mutations were enrolled. Twenty-eight patients were evaluable for efficacy. Patients had tumors with BRAF V600E (n = 26), K601E (n = 2), or other (n = 3) mutations. Two patients with CR (breast and ovarian cancers; V600E), 14 with PR (13 V600E, one N581I), and three with SD16+ (two V600E, one T599_V600insT) were observed with a DC rate of 68% (P < .0001; one-sided 90% CI, 54 to 100) and an OR rate of 57% (95% CI, 37 to 76). Nineteen patients experienced ≥one drug-related grade 3-5 adverse event or serious adverse event including one death attributed to treatment-related kidney injury. CONCLUSION: Cobimetinib plus vemurafenib showed antitumor activity in patients with advanced solid tumors with BRAF V600E mutations; additional study is warranted to confirm the antitumor activity in tumors with non-V600E BRAF mutations.

Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a pragmatic basket trial evaluating antitumor activity of approved targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from cohorts of patients with high tumor mutational burden (HTMB, defined as ≥9 mutations per megabase) with advanced colorectal cancer (CRC) and other advanced cancers treated with pembrolizumab are reported. METHODS: Eligible patients were 18 years and older with measurable tumors and a lack of standard treatment options, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. The primary end point was disease control (DC), defined as complete or partial response or stable disease (SD) of at least 16-weeks duration. For the CRC cohort, Simon's two-stage design with a null DC rate of 15% versus 35% (power = 0.85; α = .10) was used. Low accruing histology-specific cohorts were collapsed into one histology-pooled (HP) cohort. For the HP cohort, the null hypothesis of a DC rate of 15% was rejected if the lower limit of a one-sided 90% CI was >15%. Secondary end points included objective response (OR), safety, progression-free survival, overall survival, duration of response, and duration of SD. RESULTS: Seventy-seven patients with HTMB with CRC (n = 28) or advanced cancers (n = 49) were treated with pembrolizumab. For the CRC cohort, the DC rate was 31% (P = .04) and the OR rate was 11%. For the HP cohort, the DC rate was 45% (one-sided 90% CI, 35 to 100) and the OR rate was 26%. The null hypothesis of a 15% DC rate was rejected for both cohorts. Twelve of 77 patients experienced treatment-related grade 3 adverse events (AEs) or serious AEs, including two deaths. CONCLUSION: Pembrolizumab demonstrated antitumor activity in pretreated patients with advanced cancers and HTMB.

Factors Associated With Unmet Supportive Care Needs and Emergency Department Visits and Hospitalizations in Ambulatory Oncology.

Importance: Patients with cancer experience multiple supportive care needs (eg, coping and financial counseling) that, if not addressed, may result in poor clinical outcomes. Limited work has assessed the factors associated with unmet needs in large and diverse samples of ambulatory oncology patients. Objective: To characterize the factors associated with unmet supportive care needs among ambulatory oncology patients and to assess whether such needs were associated with emergency department (ED) visits and hospitalizations. Design, Setting, and Participants: Between October 1, 2019, and June 30, 2022, cross-sectional retrospective analyses were performed in a large and diverse ambulatory cancer population via My Wellness Check, an electronic health record (EHR)-based supportive care needs and patient-reported outcomes (PROs) screening and referral program. Main Outcomes and Measures: Demographic characteristics, clinical characteristics, and clinical outcomes were extracted from EHRs. Data on PROs (ie, anxiety, depression, fatigue, pain, and physical function), health-related quality of life (HRQOL), and supportive care needs were also collected. Logistic regressions examined factors associated with unmet needs. Cumulative incidence of ED visits and hospitalizations were assessed by Cox proportional hazards regression models adjusting for covariates. Results: The 5236 patients in the study had a mean (SD) age of 62.6 (13.1) years and included 2949 women (56.3%), 2506 Hispanic or Latino patients (47.9%), and 4618 White patients (88.2%); 1370 patients (26.2%) indicated Spanish as their preferred language, according to their EHR. A total of 940 patients (18.0%) reported 1 or more unmet needs. Black race (adjusted odds ratio [AOR], 1.97 [95% CI, 1.49-2.60]), Hispanic ethnicity (AOR, 1.31 [95% CI, 1.10-1.55]), 1 to 5 years after diagnosis (AOR, 0.64 [95% CI, 0.54-0.77]), more than 5 years after diagnosis (AOR, 0.60 [95% CI, 0.48-0.76]), anxiety (AOR, 2.25 [95% CI, 1.71-2.95]), depression (AOR, 2.07 [95% CI, 1.58-2.70]), poor physical function (AOR, 1.38 [95% CI, 1.07-1.79]), and low HRQOL scores (AOR, 1.89 [95% CI, 1.50-2.39]) were associated with greater unmet needs. Patients with unmet needs had a significantly higher risk of ED visits (adjusted hazard ratio [AHR], 1.45 [95% CI, 1.20-1.74]) and hospitalizations (AHR, 1.36 [95% CI, 1.13-1.63]) relative to patients without unmet needs. Conclusions and Relevance: In this cohort study of ambulatory oncology patients, unmet supportive care needs were associated with worse clinical outcomes. Patients from racial and ethnic minority groups and those with greater emotional or physical burden were more likely to have 1 or more unmet needs. Results suggest that addressing unmet supportive care needs may be crucial for improving clinical outcomes, and targeted efforts should focus on specific populations.

Symptoms and Needs Monitoring in Diverse Ambulatory Oncology Patients: Usage Characteristics and Impact on Emergency Room Visits and Hospitalization.

PURPOSE: Symptoms and needs monitoring using patient-reported outcomes (PRO) is associated with improved clinical outcomes in cancer care. However, these improvements have been observed predominantly in non-Hispanic White patients using English assessments with high completion rates. The documented impact of such monitoring on system-level outcomes including emergency room (ER) visits and hospitalizations remains limited. We explored factors affecting the completion of PRO measures and evaluated clinical outcomes in an ambulatory oncology setting with a diverse racial, ethnic, and linguistic population. METHODS: A retrospective analysis (October 2019-February 2022) was performed for patients with cancer assigned to My Wellness Check (MWC), a patient-portal-administered and electronic health record-based PRO assessment that generates automated alerts to oncology providers. Patient demographics, clinical characteristics, and clinical outcomes were collected. Logistic regression models examined factors affecting the completion of MWC questionnaires. Cumulative incidence of ER visits and hospitalization were assessed by Cox proportional hazards regression models adjusting for demographics. RESULTS: We identified 9,553 patients; 43.1% (n = 4,117) answered one or more questions. Patients age 65 years or older (adjusted odds ratio [aOR], 0.77; P < .0001), male (aOR, 0.81; P < .0001), Hispanic/Latino ethnicity (aOR, 0.70; P < .0001), living without partners (aOR, 0.75; P < .0001), or receiving no treatment (aOR, 0.76; P < .0001) were less likely to answer MWC questionnaires. Patients who completed the entire MWC questionnaires had a reduced risk of an ER visit (adjusted hazard ratio, 0.78; P < .0001) and hospitalization (adjusted hazard ratio, 0.80; P = .0007) relative to patients who did not. CONCLUSION: Completing electronic health record-based PRO assessments was associated with significantly better clinical outcomes in a diverse cancer population. Specific patient groups were less likely to participate. Further research is needed to identify barriers to completing PRO measures and the long-term benefits of such programs.

Cobimetinib Plus Vemurafenib in Patients With Colorectal Cancer With BRAF Mutations: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: TAPUR is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. The results of a cohort of patients with colorectal cancer (CRC) with BRAF mutations treated with cobimetinib (C) plus vemurafenib (V) are reported. METHODS: Eligible patients had advanced CRC, no standard treatment options, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors with BRAF V600E/D/K/R mutations, and no MAP2K1/2, MEK1/2, or NRAS mutations. C was taken 60 mg orally once daily for 21 days followed by seven days off, and V was taken 960 mg orally twice daily. Simon's two-stage design was used with a primary study end point of objective response or stable disease of at least 16 weeks duration. Secondary end points were progression-free survival, overall survival, and safety. RESULTS: Thirty patients were enrolled from August 2016 to August 2018; all had CRC with a BRAF V600E mutation except one patient with a BRAF K601E mutation. Three patients were not evaluable for efficacy. Eight patients with partial responses and six patients with stable disease of at least 16 weeks duration were observed for disease control and objective response rates of 52% (95% CI, 35 to 65) and 30% (95% CI, 14 to 50), respectively. The null hypothesis of 15% disease control rate was rejected (P < .0001). Thirteen patients had at least one grade 3 adverse event or serious adverse event at least possibly related to C + V: anemia, decreased lymphocytes, dyspnea, diarrhea, elevated liver enzymes, fatigue, hypercalcemia, hypophosphatemia, rash, photosensitivity, and upper gastrointestinal hemorrhage. CONCLUSION: The combination of C + V has antitumor activity in heavily pretreated patients with CRC with BRAF mutations.

Implementation and Feasibility of an Electronic Health Record-Integrated Patient-Reported Outcomes Symptom and Needs Monitoring Pilot in Ambulatory Oncology.

PURPOSE: Describe the feasibility and implementation of an electronic health record (EHR)-integrated symptom and needs screening and referral system in a diverse racial/ethnic patient population in ambulatory oncology. METHODS: Data were collected from an ambulatory oncology clinic at the University of Miami Health System from October 2019 to January 2021. Guided by a Patient Advisory Board and the Exploration, Preparation, Implementation, and Sustainment model, My Wellness Check was developed to assess physical and psychologic symptoms and needs of ambulatory oncology patients before appointments to triage them to supportive services when elevated symptoms (eg, depression), barriers to care (eg, transportation and childcare), and nutritional needs were identified. Patients were assigned assessments at each appointment no more than once in a 30-day period starting at the second visit. Assessments were available in English and Spanish to serve the needs of the predominantly Spanish-speaking Hispanic/Latino population. RESULTS: From 1,232 assigned assessments, more than half (n = 739 assessments; 60.0%) were initiated by 506 unique patients. A total of 65.4% of English and 49.9% of Spanish assessments were initiated. Among all initiated assessments, the majority (85.1%) were completed at home via the patient portal. The most common endorsed items were nutritional needs (32.9%), followed by emotional symptoms (ie, depression and anxiety; 27.8%), practical needs (eg, financial concerns; 21.7%), and physical symptoms (17.6%). Across the physical symptom, social work, and nutrition-related alerts, 77.1%, 99.7%, and 78.8%, were addressed, respectively, by the corresponding oncology health professional, social work team member, or nutritionist. CONCLUSION: The results demonstrate encouraging feasibility and initial acceptability of implementing an EHR-integrated symptom and needs screening and referral system among diverse oncology patients. To our knowledge, this is the first EHR-integrated symptom and needs screening system implemented in routine oncology care for Spanish-speaking Hispanics/Latinos.

Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported. METHODS: Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety. RESULTS: Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label. CONCLUSION: Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.

Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07).

In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N = 34), lapatinib (L; N = 36), or both (TL; N = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30-65%) and TL (52%, 95% CI 38-65%), and a lower pCR rate with L (25%, 95% CI 13-43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N = 110), after one cycle of HER2-targeted therapy alone (N = 89), and at time of surgery (N = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.

Cetuximab in Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Ovarian Cancer Without KRAS, NRAS, or BRAF Mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

BACKGROUND: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets. OBJECTIVE: With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations. PATIENTS AND METHODS: Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/m2 over 60 min). A Simon two-stage design, requiring ten patients in stage I, was employed per each disease-specific cohort. The primary endpoint was disease control (objective response or stable disease for at least 16 weeks). If two or more patients in stage I achieved disease control, the cohort would enroll 18 more patients in stage II. Power and alpha of the design are 85% and 10%, respectively. Secondary endpoints included progression-free survival, overall survival, and safety. RESULTS: Patients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab. CONCLUSIONS: Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations. CLINICAL TRIAL REGISTRATION: NCT02693535 (26 February, 2016).

Palbociclib in Patients With Non-Small-Cell Lung Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a phase II pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results in a cohort of patients with non-small-cell lung cancer (NSCLC) with CDKN2A alterations treated with palbociclib are reported. METHODS: Eligible patients were ≥ 18 years old with advanced NSCLC, no remaining standard treatment options, measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Patients with NSCLC with CDKN2A alterations and no Rb mutations received palbociclib 125 mg orally once daily for 21 days, followed by 7 days off. Simon's two-stage design was used with a primary study end point of objective response or stable disease (SD) of at least 16 weeks in duration. Secondary end points are progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Twenty-nine patients were enrolled from January 2017 to June 2018; two patients were not evaluable for response but were included in safety analyses. One patient with partial response and six patients with SD were observed, for a disease control rate of 31% (90% CI, 19% to 40%). Median PFS was 8.1 weeks (95% CI, 7.1 to 16.0 weeks), and median OS was 21.6 weeks (95% CI, 14.1 to 41.1 weeks). Eleven patients had at least 1 grade 3 or 4 adverse event (AE) or serious AE (SAE) possibly related to palbociclib (most common, cytopenias). Other AEs or SAEs possibly related to the treatment included anorexia, fatigue, febrile neutropenia, hypophosphatemia, sepsis, and vomiting. CONCLUSION: Palbociclib monotherapy demonstrated evidence of modest antitumor activity in heavily pretreated patients with NSCLC with CDKN2A alterations. Additional investigation is necessary to confirm efficacy and utility of palbociclib in this population.

Development of a multigenerational digital lifestyle intervention for women cancer survivors and their families.

OBJECTIVES: This paper presents the results of a study developed to inform the design of a multigenerational digital lifestyle intervention for overweight/obese women cancer survivors and their families. We followed the first six phases of the Integrate, Design, Assess, and Share (IDEAS) framework. METHODS: Grandmothers with breast, endometrial, or ovarian cancers (n = 46; 66.1 ± 0.9 years old; 34% Hispanic, 33% non-Hispanic black, 33% non-Hispanic white) self-reported their lifestyle behaviors, family structure, mobile device use, and interest in a family-based lifestyle intervention. A randomly selected subset of 21 participants subsequently completed qualitative interviews to understand their family relationships, weight-related challenges, and feedback on intervention prototypes. RESULTS: Participants reported low fruit intake (0.9 ± 0.1 servings/day), moderate vegetable intake (3.0 ± 0.2 servings/day), and high levels of moderate physical activity (990 ± 234 MET-minutes/week). The majority owned a smartphone (93%) and expressed interest in family-based programs (80%) that focused on weight management (91%). Qualitative data were collapsed into seven intervention considerations, including: capitalizing on existing familial support, involving local family who need lifestyle change, tapping into survivors' internal strengths, validating prior weight loss, overcoming barriers to sustained lifestyle change, providing information on cancer risk, and motivating families through reinforcing activities. CONCLUSIONS: Following the IDEAS framework, our next steps are to develop a fully-functioning prototype and conduct a randomized pilot trial to test the feasibility and effects of a digital intervention that empowers racially/ethnically diverse overweight/obese women cancer survivors to improve their physical activity and dietary intake and to lose weight by encouraging healthy lifestyle behaviors in their children and grandchildren.

Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer.

BACKGROUND: Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. METHODS: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. RESULTS: Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p = 0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR = 0.23; p = 0.04). CONCLUSIONS: These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00005970 . Registered on July 5, 2000.

Improved Survival of HER2+ Breast Cancer Patients Treated with Trastuzumab and Chemotherapy Is Associated with Host Antibody Immunity against the HER2 Intracellular Domain.

The addition of trastuzumab to chemotherapy extends survival among patients with HER2(+) breast cancer. Prior work showed that trastuzumab and chemotherapy augments HER2 extracellular domain (ECD)-specific antibodies. The current study investigated whether combination therapy induced immune responses beyond HER2-ECD and, importantly, whether those immune responses were associated with survival. Pretreatment and posttreatment sera were obtained from 48 women with metastatic HER2(+) breast cancer on NCCTG (now Alliance for Clinical Trials in Oncology) studies, N0337 and N983252. IgG to HER2 intracellular domain (ICD), HER2-ECD, p53, IGFBP2, CEA, and tetanus toxoid were examined. Sera from 25 age-matched controls and 26 surgically resected HER2(+) patients were also examined. Prior to therapy, some patients with metastatic disease had elevated antibodies to IGFBP2, p53, HER2-ICD, HER2-ECD, and CEA, but not to tetanus toxin, relative to controls and surgically resected patients. Treatment augmented antibody responses to HER2-ICD in 69% of metastatic patients, which was highly associated with improved progression-free survival (PFS; HR = 0.5, P = 0.0042) and overall survival (OS; HR = 0.7, P = 0.038). Augmented antibody responses to HER2-ICD also correlated (P = 0.03) with increased antibody responses to CEA, IGFBP2, and p53, indicating that treatment induces epitope spreading. Paradoxically, patients who already had high preexisting immunity to HER2-ICD did not respond to therapy with increased antibodies to HER2-ICD and demonstrated poorer PFS (HR = 1.6, P < 0.0001) and OS (HR = 1.4, P = 0.0006). Overall, the findings further demonstrate the importance of the adaptive immune system in the efficacy of trastuzumab-containing regimens. Cancer Res; 76(13); 3702-10. ©2016 AACR.

Delivery of NKG2D ligand using an anti-HER2 antibody-NKG2D ligand fusion protein results in an enhanced innate and adaptive antitumor response.

NKG2D ligands link the innate and adapative immune response by activating the receptors expressed on effector cells of both the innate (NK) and adaptive immune systems (CD8(+) T cells). In this study, we explored the potential therapeutic utility of this intersection by fusing the murine NKG2D ligand Rae-1ß to the 3' end of an anti-HER2 IgG3 antibody containing an intact Fc domain (anti-HER2 IgG3-Rae-1ß), thereby targeting an NK cell activation signal to HER2+ breast tumor cells. The antitumor efficacy of this anti-HER2-Rae-1ß fusion protein was examined in a mouse mammary tumor model engineered to express HER2 (EMT6-HER2 cells). We observed an enhanced cytotoxic response of NK effectors against EMT-HER2 cells in vitro. Mice implanted on one flank with EMT6-HER2 cells and contralaterally with control EMT6 cells exhibited rapid regression of EMT6-HER2 tumors but delayed regression of contralateral EMT6 tumors. IFNγ was implicated, given a lack of antitumor efficacy in IFNγ(-/-) mice. Depletion of either NK cells or CD8(+) T cells abrogated tumor growth inhibition, suggesting essential roles for each in the observed antitumor activity. Mice rejecting EMT6-HER2 tumors after anti-HER2-Rae-1ß treatment showed markedly decreased tumor growth when rechallenged with EMT6-HER2 or EMT6 cells, whereas both EMT6 and EMT6-HER2 cells grew in control mice, indicating the development of an adaptive memory response. Our findings demonstrate that administration of an antibody-NKG2D ligand fusion protein can enhance innate and adaptive immune antitumor responses, also evoking additional nontargeted antigens to enhance the potential clinical utility of this approach.

Ocular involvement as the initial manifestation of T-cell chronic lymphocytic leukemia.

PURPOSE: To present a case of T-cell chronic lymphocytic leukemia (T-CLL) manifesting as an intraocular lymphoma. DESIGN: Interventional case report. METHODS: We performed a vitreous biopsy in a 67-year-old woman who presented with blurred vision and vitreous cellular infiltration. Morphologic, immunohistochemical, flow cytometry, and molecular analysis by polymerase chain reaction of vitreous fluid, peripheral blood, bone marrow aspirate, and biopsy were performed. RESULTS: Cytofluorographic and molecular analysis of vitreous cells demonstrated a monoclonal T-cell population consistent with a T-cell intraocular lymphoma. Systemic evaluation established diagnosis of T-cell CLL. CONCLUSION: T-CLL is a rare disease with an aggressive clinical course. We present a case of T-cell intraocular lymphoma as the initial manifestation of an otherwise asymptomatic T-CLL.