Shannon Puhalla

A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas

Purpose: Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Experimental Design: Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Results: Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. Conclusions: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma. Clin Cancer Res; 18(6); 1726–34. ©2012 AACR.

Prediction of the Oncotype DX recurrence score: use of pathology-generated equations derived by linear regression analysis

Oncotype DX is a commercial assay frequently used for making chemotherapy decisions in estrogen receptor (ER)-positive breast cancers. The result is reported as a recurrence score ranging from 0 to 100, divided into low-risk (<18), intermediate-risk (18–30), and high-risk (≥31) categories. Our pilot study showed that recurrence score can be predicted by an equation incorporating standard morphoimmunohistologic variables (referred to as original Magee equation). Using a data set of 817 cases, we formulated three additional equations (referred to as new Magee equations 1, 2, and 3) to predict the recurrence score category for an independent set of 255 cases. The concordance between the risk category of Oncotype DX and our equations was 54.3%, 55.8%, 59.4%, and 54.4% for original Magee equation, new Magee equations 1, 2, and 3, respectively. When the intermediate category was eliminated, the concordance increased to 96.9%, 100%, 98.6%, and 98.7% for original Magee equation, new Magee equations 1, 2, and 3, respectively. Even when the estimated recurrence score fell in the intermediate category with any of the equations, the actual recurrence score was either intermediate or low in more than 80% of the cases. Any of the four equations can be used to estimate the recurrence score depending on available data. If the estimated recurrence score is clearly high or low, the oncologists should not expect a dramatically different result from Oncotype DX, and the Oncotype DX test may not be needed. Conversely, an Oncotype DX result that is dramatically different from what is expected based on standard morphoimmunohistologic variables should be thoroughly investigated.

Sensitive Detection of Mono- and Polyclonal ESR1 Mutations in Primary Tumors, Metastatic Lesions, and Cell-Free DNA of Breast Cancer Patients

Purpose: Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell-free DNA (cfDNA). Experimental Design: Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (n = 43), bone (n = 12) and brain metastases (n = 38), and cfDNA (n = 29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. Results: ESR1 mutations were detected for D538G (n = 13), Y537S (n = 3), and Y537C (n = 1), and not for K303R, S463P, or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3% to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (n = 5), mutations were detected in both (n = 3) or in cfDNA only (n = 2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. Conclusions: ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare ESR1-mutant clones are enriched by endocrine therapy. Further studies should address whether sensitive detection of ESR1 mutations in primary breast cancer and in serial blood draws may be predictive for development of resistant disease. Clin Cancer Res; 22(5); 1130–7. ©2015 AACR. See related commentary by Gu and Fuqua, p. 1034

Translational breast cancer research consortium (TBCRC) 022: A phase II trial of neratinib 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 in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. PATIENTS AND METHODS Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders. RESULTS Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. CONCLUSION Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

BRCA 1/2-Mutation Related and Sporadic Breast and Ovarian Cancers: More Alike than Different

No longer is histology solely predictive of cancer treatment and outcome. There is an increasing influence of tumor genomic characteristics on therapeutic options. Both breast and ovarian cancers are at higher risk of development in patients with BRCA 1/2-germline mutations. Recent data from The Cancer Genome Atlas and others have shown a number of genomic similarities between triple negative breast cancers (TNBCs) and ovarian cancers. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in hereditary BRCA 1/2-mutated and sporadic breast and ovarian cancers. In this review, we will summarize the current literature regarding the genomic and phenotypic similarities between BRCA 1/2-mutation related cancers, sporadic TNBCs, and sporadic ovarian cancers. We will also review Phase I, II, and III data using PARP inhibitors for these malignancies and compare and contrast the results with respect to histology.

Hormonal therapy in breast cancer: A model disease for the personalization of cancer care

The treatment of breast cancer is driven by subtype classification, of which the assessment of hormone receptor status is one of the important determinants of therapy. The use of hormonal therapy to treat estrogen‐receptor positive breast cancer has been studied for over a century and is one of the well‐described uses of personalized medicine. In this review, we will describe the classification of hormone receptor status and the various endocrine treatment strategies. Opportunities for personalization of care are illustrated.

Intrinsic Subtype Switching and Acquired ERBB2/HER2 Amplifications and Mutations in Breast Cancer Brain Metastases

Importance Patients with breast cancer (BrCa) brain metastases (BrM) have limited therapeutic options. A better understanding of molecular alterations acquired in BrM could identify clinically actionable metastatic dependencies. Objective To determine whether there are intrinsic subtype differences between primary tumors and matched BrM and to uncover BrM-acquired alterations that are clinically actionable. Design, Setting, and Participants In total, 20 cases of primary breast cancer tissue and resected BrM (10 estrogen receptor [ER]-negative and 10 ER-positive) from 2 academic institutions were included. Eligible cases in the discovery cohort harbored patient-matched primary breast cancer tissue and resected BrM. Given the rarity of patient-matched samples, no exclusion criteria were enacted. Two validation sequencing cohorts were used—a published data set of 17 patient-matched cases of BrM and a cohort of 7884 BrCa tumors enriched for metastatic samples. Main Outcomes and Measures Brain metastases expression changes in 127 genes within BrCa signatures, PAM50 assignments, and ERBB2/HER2 DNA-level gains. Results Overall, 17 of 20 BrM retained the PAM50 subtype of the primary BrCa. Despite this concordance, 17 of 20 BrM harbored expression changes (<2-fold or >2-fold) in clinically actionable genes including gains of FGFR4 (n = 6 [30%]), FLT1 (n = 4 [20%]), AURKA (n = 2 [10%]) and loss of ESR1 expression (n = 9 [45%]). The most recurrent expression gain was ERBB2/HER2, which showed a greater than 2-fold expression increase in 7 of 20 BrM (35%). Three of these 7 cases were ERBB2/HER2-negative out of 13 ERBB2/HER2-negative in the primary BrCa cohort and became immunohistochemical positive (3+) in the paired BrM with metastasis-specific amplification of the ERBB2/HER2 locus. In an independent data set, 2 of 9 (22.2%) ERBB2/HER2-negative BrCa switched to ERBB2/HER2-positive with 1 BrM acquiring ERBB2/HER2 amplification and the other showing metastatic enrichment of the activating V777L ERBB2/HER2 mutation. An expanded cohort revealed that ERBB2/HER2 amplification and/or mutation frequency was unchanged between local disease and metastases across all sites; however, a significant enrichment was appreciated for BrM (13% local vs 24% BrM; P < .001). Conclusions and Relevance Breast cancer BrM commonly acquire alterations in clinically actionable genes, with metastasis-acquired ERBB2/HER2 alterations in approximately 20% of ERBB2/HER2-negative cases. These observations have immediate clinical implications for patients with ERBB2/HER2–negative breast cancer and support comprehensive profiling of metastases to inform clinical care.

Unsanctifying the sanctuary: challenges and opportunities with brain metastases

While the use of targeted therapies, particularly radiosurgery, has broadened therapeutic options for CNS metastases, patients respond minimally and prognosis remains poor. The inability of many systemic chemotherapeutic agents to penetrate the blood-brain barrier (BBB) has limited their use and allowed brain metastases to become a burgeoning clinical challenge. Adequate preclinical models that appropriately mimic the metastatic process, the BBB, and blood-tumor barriers (BTB) are needed to better evaluate therapies that have the ability to enhance delivery through or penetrate into these barriers and to understand the mechanisms of resistance to therapy. The heterogeneity among and within different solid tumors and subtypes of solid tumors further adds to the difficulties in determining the most appropriate treatment approaches and methods of laboratory and clinical studies. This review article discusses therapies focused on prevention and treatment of CNS metastases, particularly regarding the BBB, and the challenges and opportunities these therapies present.

Adjuvant endocrine therapy for premenopausal women with breast cancer

AIMS Endocrine therapy is a pivotal treatment for women with hormone-receptor positive breast cancer. In premenopausal women, endocrine therapy primarily consists of tamoxifen and ovarian suppressive strategies. Younger women experience improvements in the risks of relapse or death from breast cancer with the use of chemotherapy as well, with part of this benefit explained by resultant premature amenorrhea. Unfortunately despite a centuries worth of clinical trials, the most efficacious combination of hormonal therapies and chemotherapy has yet to be determined. This paper serves as a comprehensive review of the substantial data in the adjuvant treatment of premenopausal, hormone receptor-positive women with breast cancer. METHODS AND RESULTS PubMed and American Society of Clinical Oncology (ASCO) Proceedings searches from 1896 to present were performed. All of the trials examining the role of ovarian suppression and tamoxifen with and without chemotherapy in premenopausal women were included. The current data suggests that endocrine therapy can be an important alternative to chemotherapy in select patient populations, and improvements in outcome are also seen with the combination of hormonal and chemotherapy strategies in other populations. A majority of the trials examined did not use what is considered to be current standards of care regarding chemotherapy regimens and durations of adjuvant hormonal therapy. Many unanswered questions remain particularly regarding the combined use of ovarian suppression and tamoxifen in women who are also receiving chemotherapy. CONCLUSION There is a persistent need to define optimal endocrine therapy in premenopasusal women with hormone-receptor positive breast cancer. Contemporaneous trials, such as the SOFT trial will provide direction, and additional biomarker and pharmacogenomic data will further supplement individualized patient decision making.

The Attitudes, Communication, Treatment, and Support Intervention to Reduce Breast Cancer Treatment Disparity

PURPOSE/OBJECTIVES to test the effect of a supportive, one-time psychoeducational intervention on treatment adherence among African American women receiving first adjuvant therapy for breast cancer. DESIGN a pilot, randomized, controlled clinical trial, two-group design, with one-time intervention and four data collection points. SETTING two University of Pittsburgh Cancer Institute clinics. SAMPLE 24 African American women. METHODS the Attitudes, Communication, Treatment, and Support (ACTS) intervention is a 45-minute one-on-one session with an African American woman recommended to have chemotherapy for breast cancer. The interventionist is an African American breast cancer survivor. The intervention consists of a discussion about chemotherapy and the importance of communicating knowledge needs and distress, an explanation of the specific treatment plan according to pathology, and support through the survivor testimonial and video clips from the African American community. MAIN RESEARCH VARIABLES dose of chemotherapy received and dose of chemotherapy prescribed. FINDINGS Twenty patients completed chemotherapy, and four chose not to begin or discontinued recommended chemotherapy. The groups were equal in key sociodemographic variables. Compared to usual care, the ACTS intervention participants demonstrated trends toward initiation of chemotherapy (100% versus 82%), overall adherence to chemotherapy (92% versus 73%), and percentage of total dose of chemotherapy received or prescribed (94% versus 74%). Compared to usual care, the ACTS intervention participants demonstrated more rapid initiation of chemotherapy and better overall adherence to chemotherapy. CONCLUSIONS the pilot ACTS intervention shows promise as a psychoeducational intervention to assist with chemotherapy decision making among African American women. IMPLICATIONS FOR NURSING African American women are at high risk of not receiving the full dose of prescribed chemotherapy for breast cancer for multiple reasons. Nurses must be sensitive to the unique fears and concerns of this population regarding chemotherapy decisions. An intervention addressing these fears and concerns may help to increase adherence.