A mixed-methods study to inform development of a caregiver-specific problem list for cancer distress screening.

OBJECTIVE: Oncology guidelines for distress management recommend use of the single-item distress thermometer (DT) and accompanying Problem List (PL) to identify patients with high distress levels and their potential sources of distress. However, oncology practices have yet to establish standardized protocols to screen and triage caregivers with high distress levels. With an eye toward integrating caregiver-centered support services into cancer care, this mixed-methods study sought to assess caregiver distress and challenges that may contribute to their distress. METHODS: Nineteen caregivers of metastatic breast cancer patients (60% female, 47% ethnic/racial minority) completed an interview and a survey comprised of the DT, the original 39-item PL, and five additional caregiver-specific PL items. RESULTS: Caregivers reported moderate distress levels and more than half exceeded the National Comprehensive Cancer Network (NCCN) cut-off, denoting significant distress. There was no association between caregiver distress and the number of items endorsed on the original PL. Qualitative analysis identified nine problem domains as areas of caregiver unmet need needs (i.e., practical challenges, caregiving responsibilities, social/relationship issues, caregiver and patient emotional well-being, caregiver and patient physical well-being, spiritual well-being, and communication). Two of the problem domains (caregiving responsibilities and communication) were not captured in any way by the original PL. CONCLUSION: With further research and development, the identified domains could serve as the basis for a caregiver-specific PL to facilitate triage and referral when incorporated as part of routine distress screening.

A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer.

PURPOSE: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-"addicted" tumors who may benefit from a chemotherapy-sparing strategy. EXPERIMENTAL DESIGN: Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor-positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based PAM50, and targeted DNA-sequencing. GPA cutoffs and classifier of response were constructed in TBCRC023 using a decision tree algorithm, then validated in PAMELA. RESULTS: In TBCRC023, 72 breast cancer specimens had GPA, PAM50, and sequencing data, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio ≥ 4.6 and %3+ IHC staining ≥ 97.5%. With PAM50 and sequencing data, the model added HER2-E and PIK3CA wild-type (WT). For clinical implementation, the classifier was locked as HER2 ratio ≥ 4.5, %3+ IHC staining ≥ 90%, and PIK3CA-WT and HER2-E, yielding 55% and 94% positive (PPV) and negative (NPV) predictive values, respectively. Independent validation using 44 PAMELA cases with all three biomarkers yielded 47% PPV and 82% NPV. Importantly, our classifier's high NPV signifies its strength in accurately identifying patients who may not be good candidates for treatment deescalation. CONCLUSIONS: Our multiparameter classifier differentially identifies patients who may benefit from HER2-targeted therapy alone from those who need chemotherapy and predicts pCR to anti-HER2 therapy alone comparable with chemotherapy plus dual anti-HER2 therapy in unselected patients.

Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: Analysis of TBCRC 038 and RAHBT cohorts.

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We perform multiscale, integrated molecular profiling of DCIS with clinical outcomes by analyzing 774 DCIS samples from 542 patients with 7.3 years median follow-up from the Translational Breast Cancer Research Consortium 038 study and the Resource of Archival Breast Tissue cohorts. We identify 812 genes associated with ipsilateral recurrence within 5 years from treatment and develop a classifier that predicts DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions are identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

Prognostic Impact of Radiation Therapy in Pure Mucinous Breast Carcinoma.

PURPOSE: Pure Mucinous breast carcinoma (PMBC) is an invasive breast cancer with favorable prognosis. While pathology-specific guidelines exist for PMBC regarding adjuvant chemotherapy and endocrine therapy, no recommendations exist regarding locoregional treatment based on tumor histology. Prognostic impact of radiotherapy for patients with PMBC remains unclear. MATERIALS AND METHODS: The National Cancer Database was queried (2004-2017) for patients with pN0M0 PMBC who underwent lumpectomy. Chi-square testing compared categorical frequencies between patients who received radiotherapy versus those who did not. Propensity score matching created a 1:1 matched cohort of patients who received radiotherapy and patients who didn't. Kaplan-Meier analysis evaluated overall survival (OS). Cox proportional hazard analyses identified clinical and treatment factors prognostic for OS. RESULTS: 17,259 patients met selection criteria; 11,087 (74%) received radiotherapy while 3852 (26%) did not. After PSM, radiotherapy (HR 0.629; 95% CI 0.531-0.746), endocrine therapy (HR 0.676; 95% CI 0.567-0.805), black race (HR 0.703; 95% CI 0.498-0.991), and private insurance (HR 0.184; 95% CI 0.078-0.432) were favorable prognostic factors on multivariate Cox regression analysis while age ≥ 70 years (HR 2.668; 95% CI 1.903-3.740), tumor size > 20 mm (HR 1.964; 95% CI 1.613-2.391), and CDCC score > 0 (HR 1.770; 95% CI 1.474-2.126) were unfavorable prognostic factors. After PSM, 5-year OS was 86% for those who received radiotherapy and 81% for those who did not (P < .001). CONCLUSION: This is the largest study to date on PMBC and the prognostic impact of adjuvant radiotherapy. Radiotherapy is associated with a survival advantage, suggesting omission of radiotherapy is not warranted.

Proteogenomic Markers of Chemotherapy Resistance and Response in Triple-Negative Breast Cancer.

Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin and docetaxel combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pretreatment patient biopsies uniquely revealed metabolic pathways, including oxidative phosphorylation, adipogenesis, and fatty acid metabolism, that were associated with resistance. Both proteomics and transcriptomics revealed that sensitivity was marked by elevation of DNA repair, E2F targets, G2-M checkpoint, interferon-gamma signaling, and immune-checkpoint components. Proteogenomic analyses of somatic copy-number aberrations identified a resistance-associated 19q13.31-33 deletion where LIG1, POLD1, and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I) gene deletion and/or low mRNA expression levels were associated with lack of pathologic complete response, higher chromosomal instability index (CIN), and poor prognosis in TNBC, as well as carboplatin-selective resistance in TNBC preclinical models. Hemizygous loss of LIG1 was also associated with higher CIN and poor prognosis in other cancer types, demonstrating broader clinical implications. SIGNIFICANCE: Proteogenomic analysis of triple-negative breast tumors revealed a complex landscape of chemotherapy response associations, including a 19q13.31-33 somatic deletion encoding genes serving lagging-strand DNA synthesis (LIG1, POLD1, and XRCC1), that correlate with lack of pathologic response, carboplatin-selective resistance, and, in pan-cancer studies, poor prognosis and CIN. This article is highlighted in the In This Issue feature, p. 2483.

Multi-antigen-targeted T-cell therapy to treat patients with relapsed/refractory breast cancer.

Purpose: Adoptively transferred, ex vivo expanded multi-antigen-targeted T cells (multiTAA-T) represent a new, potentially effective, and nontoxic therapeutic approach for patients with breast cancer (BC). In this first-in-human trial, we investigated the safety and clinical effects of administering multiTAA T cells targeting the tumor-expressed antigens, Survivin, NY-ESO-1, MAGE-A4, SSX2, and PRAME, to patients with relapsed/refractory/metastatic BC. Materials and methods: MultiTAA T-cell products were generated from the peripheral blood of heavily pre-treated patients with metastatic or locally recurrent unresectable BC of all subtypes and infused at a fixed dose level of 2 × 107/m2. Patients received two infusions of cells 4 weeks apart and safety and clinical activity were determined. Cells were administered in an outpatient setting and without prior lymphodepleting chemotherapy. Results: All patients had estrogen receptor/progesterone receptor positive BC, with one patient also having human epidermal growth factor receptor 2-positive. There were no treatment-related toxicities and the infusions were well tolerated. Of the 10 heavily pre-treated patients enrolled and infused with multiTAA T cells, nine had disease progression while one patient with 10 lines of prior therapies experienced prolonged (5 months) disease stabilization that was associated with the in vivo expansion and persistence of T cells directed against the targeted antigens. Furthermore, antigen spreading and the endogenous activation of T cells directed against a spectrum of non-targeted tumor antigens were observed in 7/10 patients post-multiTAA infusion. Conclusion: MultiTAA T cells were well tolerated and induced disease stabilization in a patient with refractory BC. This was associated with in vivo T-cell expansion, persistence, and antigen spreading. Future directions of this approach may include additional strategies to enhance the therapeutic benefit of multiTAA T cells in patients with BC.

The Phase II MutHER Study of Neratinib Alone and in Combination with Fulvestrant in HER2-Mutated, Non-amplified Metastatic Breast Cancer.

PURPOSE: HER2 mutations (HER2mut) induce endocrine resistance in estrogen receptor-positive (ER+) breast cancer. PATIENTS AND METHODS: In this single-arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ER+/HER2mut, HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n = 24) or fulvestrant-naïve cohort (n = 11). Patients with ER-negative (ER-)/HER2mut MBC received neratinib monotherapy in an exploratory ER- cohort (n = 5). RESULTS: The clinical benefit rate [CBR (95% confidence interval)] was 38% (18%-62%), 30% (7%-65%), and 25% (1%-81%) in the fulvestrant-treated, fulvestrant-naïve, and ER- cohorts, respectively. Adding trastuzumab at progression in 5 patients resulted in three partial responses and one stable disease ≥24 weeks. CBR appeared positively associated with lobular histology and negatively associated with HER2 L755 alterations. Acquired HER2mut were detected in 5 of 23 patients at progression. CONCLUSIONS: Neratinib and fulvestrant are active for ER+/HER2mut MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2mut MBC.

Dose-reduced trastuzumab deruxtecan can be safely used in liver failure and active leptomeningeal metastases.

Trastuzumab deruxtecan has been shown to have responses in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, the safety of this medication in patients with severe liver dysfunction and untreated or symptomatic central nervous system metastases is unknown. We describe a patient with metastatic HER2-positive breast cancer with liver failure and leptomeningeal metastases who was treated with dose-reduced trastuzumab deruxtecan. With treatment, the patient's hyperbilirubinemia resolved and she demonstrated a response on imaging. She was dose-escalated to full dose with minimal adverse events.

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022.

PURPOSE: This pilot study was performed to test our ability to administer neratinib monotherapy before clinically recommended craniotomy in patients with HER2-positive metastatic breast cancer to the central nervous system, to examine neratinib's central nervous system penetration at craniotomy, and to examine postoperative neratinib maintenance. PATIENTS AND METHODS: Patients with HER2-positive brain metastases undergoing clinically indicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once a day for 7 to 21 days preoperatively, and resumed therapy postoperatively in 28-day cycles. Exploratory evaluations of time to disease progression, survival, and correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. The study was registered at ClinicalTrials.gov under number NCT01494662. RESULTS: We enrolled 5 patients between May 22, 2013, and October 18, 2016. As of March 1, 2019, patients had remained on the study protocol for 1 to 75+ postoperative cycles pf therapy. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib; nonetheless, 2 patients continued to receive therapy without disease progression for at least 13 cycles, with one on-study treatment lasting for nearly 6 years. Neratinib distribution in surgical tissue was variable for 1 patient, while specimens from 2 others did not produce conclusive results as a result of limited available samples. CONCLUSION: Neratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients receiving the study treatment for durable periods. Although logistically challenging, we were able to test a limited number of CSF- and parenchymal-based neratinib concentrations. Our findings from resected tumor tissue in one patient revealed heterogeneity in drug distribution and tumor histopathology.

TBCRC 032 IB/II Multicenter Study: Molecular Insights to AR Antagonist and PI3K Inhibitor Efficacy in Patients with AR+ Metastatic Triple-Negative Breast Cancer.

PURPOSE: Preclinical data demonstrating androgen receptor (AR)-positive (AR+) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR+ (≥10%) breast cancer. PATIENTS AND METHODS: Phase Ib patients [estrogen receptor positive (ER+) or TNBC] with AR+ breast cancer received 160 mg enzalutamide in combination with taselisib to determine dose-limiting toxicities and the maximum tolerated dose (MTD). Phase II TNBC patients were randomized to receive either enzalutamide alone or in combination with 4 mg taselisib until disease progression. Primary endpoint was clinical benefit rate (CBR) at 16 weeks. RESULTS: The combination was tolerated, and the MTD was not reached. The adverse events were hyperglycemia and skin rash. Overall, CBR for evaluable patients receiving the combination was 35.7%, and median progression-free survival (PFS) was 3.4 months. Luminal AR (LAR) TNBC subtype patients trended toward better response compared with non-LAR (75.0% vs. 12.5%, P = 0.06), and increased PFS (4.6 vs. 2.0 months, P = 0.082). Genomic analyses revealed subtype-specific treatment response, and novel FGFR2 fusions and AR splice variants. CONCLUSIONS: The combination of enzalutamide and taselisib increased CBR in TNBC patients with AR+ tumors. Correlative analyses suggest AR protein expression alone is insufficient for identifying patients with AR-dependent tumors and knowledge of tumor LAR subtype and AR splice variants may identify patients more or less likely to benefit from AR antagonists.

Clinical presentation, national practice patterns, and outcomes of breast adenomyoepithelioma.

Breast adenomyoepithelioma (AME) is a rare tumor with the published literature mainly in the form of case reports. Thus, there is currently only limited published data to guide evidence-based management. We sought to use a large, contemporary US database to evaluate how these patients are managed and describe expected outcomes. The National Cancer Database was queried (2004-2013) for women with AME. Statistics included multivariable logistic regression, Kaplan-Meier analysis to evaluate overall survival (OS) and Cox proportional hazards modeling. Overall, 110 patients were analyzed. At diagnosis, the median age was 67 years and the median tumor size was 2.0 cm. All but four patients had node-negative disease. A majority (55%) of tumors were estrogen receptor negative, and only one was positive for HER2/neu. The most common surgical procedure was lumpectomy (60%); a minority (10.9%) of subjects underwent complete axillary nodal dissection, with one-quarter not undergoing pathologic nodal sampling. Chemotherapy, hormonal therapy, and radiotherapy were utilized in a minority of patients (26%, 8%, and 36%, respectively), and none were associated with OS. At median follow-up of 52 months, the 5-year OS for the entire population was 74.4%. Disease-related characteristics and practice patterns are described for AME, the largest study of this rare tumor to date. Resection is the most important aspect of management, and based on this dataset the low rate of nodal involvement suggests that in some cases nodal sampling could be safely omitted. Adjuvant therapy may be considered on a case-by-case basis. Taken together, these data provide valuable insight into a rare neoplasm that may better inform management of these patients.

TBCRC023: A Randomized Phase II Neoadjuvant Trial of Lapatinib Plus Trastuzumab Without Chemotherapy for 12 versus 24 Weeks in Patients with HER2-Positive Breast Cancer.

PURPOSE: Prior neoadjuvant trials with 12 weeks of dual anti-HER2 therapy without chemotherapy demonstrated a meaningful pathologic complete response (pCR) in patients with HER2-positive breast cancer. In this trial, we sought to determine whether longer treatment would increase the rate of pCR. PATIENTS AND METHODS: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon phase II design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2-positive breast tumors measuring ≥2 cm (median = 5 cm) were randomized in a 1:2 ratio to 12 versus 24 weeks of lapatinib and trastuzumab. Letrozole (along with ovarian suppression if premenopausal) was administered in patients whose tumors were also estrogen receptor (ER) positive. All evaluable patients were assessed for in-breast pCR. RESULTS: Ninety-seven patients were enrolled (33 in 12-week arm and 64 in 24-week arm), of whom 94 were evaluable. Median age was 51 years, and 55% were postmenopausal. Median tumor size was 5 cm, and 65% were ER-positive. The rate of pCR in the 24-week arm was 28% and numerically superior to the 12-week arm (12%). This was driven by increased pCR in the ER-positive subgroup (33% vs. 9%). Study treatment was well tolerated, with grade 1-2 diarrhea and acneiform rash being the most common toxicities. CONCLUSIONS: Treatment with dual anti-HER2 therapy for 24 weeks led to a numeric increase in pCR rate in women with HER2-positive breast cancer, without using chemotherapy. If validated, this approach may help identify patients who may benefit from deescalation of therapy.

Randomized controlled trial of high-dose versus standard-dose vitamin D3 for prevention of aromatase inhibitor-induced arthralgia.

PURPOSE: Half of hormone receptor-positive (HR+) breast cancer patients will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA), while taking aromatase inhibitor therapy. Though there is no universally accepted effective treatment for AIA, there has been some evidence to support high-dose vitamin D as a treatment. METHODS: We randomized post-menopausal women who were beginning adjuvant AI therapy to receive standard-dose vitamin D3 (800 IU daily for 52 weeks), or high-dose vitamin D3 (50,000 IU weekly for 12 weeks, followed by 2000 IU daily for 40 weeks). The primary end point was development of AIA. The trial was designed to enroll 184 patients. This futility analysis was performed after 93 patients were enrolled. RESULTS: The high-dose vitamin D regimen was effective in raising serum vitamin D levels, but there was no significant difference in development of AIA between the two arms. In the high-dose arm, 25 patients (54%) developed AIA, compared to 27 patients (57%) in the standard-dose arm. The planned futility analysis was positive; thus, the study was terminated. Neither baseline vitamin D nor 12-week vitamin D level was predictive of AIA development. CONCLUSION: Although vitamin D levels were increased in the high-dose arm, there was no significant signal for benefit of high-dose vitamin D supplementation for AIA prevention in this unblinded trial. This study, along with several others, implies that vitamin D likely does not play a significant role in AIA for the majority of patients.

TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

PURPOSE: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS AND METHODS: Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m2 twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS: Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B).Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.

Hair disorders in patients with cancer.

Cytotoxic chemotherapies, molecularly targeted therapies, immunotherapies, radiotherapy, stem cell transplants, and endocrine therapies may lead to hair disorders, including alopecia, hirsutism, hypertrichosis, and pigmentary and textural hair changes. The mechanisms underlying these changes are varied and remain incompletely understood, hampering the development of preventive or therapeutic guidelines. The psychosocial impact of chemotherapy-induced alopecia has been well documented primarily in the oncology literature; however, the effect of other alterations, such as radiation-induced alopecia, hirsutism, and changes in hair color or texture on quality of life have not been described. This article reviews clinically significant therapy-related hair disorders in oncology patients, including the underlying pathophysiological mechanisms, severity grading scales, patient-reported quality of life questionnaires, management strategies, and future translational research opportunities.

A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease.

Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I-III breast cancer, DCIS/LCIS, Paget's disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1ß, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203-14. ©2018 AACRSee related editorial by Fabian and Kimler, p. 187.