Sarika Jain

Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse

BACKGROUND Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence. PATIENTS AND METHODS This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs. RESULTS Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%-96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%). CONCLUSIONS TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.

Eribulin mesylate in the treatment of metastatic breast cancer

The treatment of metastatic breast cancer (MBC) has become increasingly challenging as the primary goals of therapy include prolonging life without added toxicity. While multiple agents are approved for the therapy of MBC, there is no standard approach for therapy beyond the second-line. Eribulin mesylate, an analog of the marine sponge halichondrin B, is a non-taxane microtubule dynamics inhibitor with a mechanism of action distinct from other tubulin-targeted drugs. Based on a significant extension in overall survival seen in a Phase III clinical trial, eribulin was approved for third-line therapy in MBC patients following anthracycline and taxane failure. Eribulin has a manageable toxicity profile and a low incidence of peripheral neuropathy. In this review, we discuss the natural source of eribulin, pharmacology, mode of action, preclinical and clinical data, and patient-focused perspectives.

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer

While identifying genomic alterations in tumor tissue is the current gold-standard technique for molecular profiling, circulating tumor DNA (ctDNA) represents a noninvasive method of assessing genomic alterations using peripheral blood. The concordance of genomic alterations between two commercially available ctDNA and tissue biopsies was compared in 45 patients with breast cancer using paired next-generation sequencing tissue and ctDNA biopsies. Across all genes, concordance between the two platforms was 91.0% to 94.2%. When only considering genomic alterations in either assay (e.g., excluding wild type/wild type genes), concordance was 10.8% to 15.1% with full plus partial concordance of 13.8% to 19.3%. Concordant mutations were associated with significantly higher variant allele frequency. Over half of mutations detected in either technique were not detected using the other biopsy technique. Including variants of unknown significance, the average number of alterations per patient was significantly higher for tissue (4.56) compared with ctDNA (2.16). When eliminating alterations not detectable in the ctDNA assay, mean number of alterations for tissue and ctDNA was similar (2.67 for tissue, 2.16 for ctDNA). Across five representative genes (TP53, PIK3CA, ERBB2, BRCA1, and BRCA2), sensitivity and specificity were 35.7% and 95.0%, respectively. Concordance when genomic alterations was detected in either tissue or ctDNA was low with each technique detecting a significant amount of nonoverlapping mutations. Potential explanations for the lack of concordance include tumor heterogeneity, different sequencing techniques, spatial and temporal factors, and potential germline DNA contamination. The study indicates that both tissue and blood-based NGS may be necessary to describe the complex biology of breast cancer. Mol Cancer Ther; 16(7); 1412–20. ©2017 AACR.

The Application of Oncotype DX in Early-Stage Lymph-Node-Positive Disease

The recurrence score derived from the 21-gene Oncotype DX assay is both prognostic and predictive of adjuvant chemotherapy benefit in node-negative, estrogen-receptor-positive breast cancer patients treated with tamoxifen. This has led to a remarkable shift in the treatment paradigm, with a sizeable number of patients being able to avoid adjuvant chemotherapy. The recurrence score was then analyzed in a large retrospective study with node-positive, estrogen-receptor-positive patients, in which it demonstrated both prognostic and predictive abilities. This review introduces the clinical trials that validated the Oncotype DX assay in the node-negative population, highlights the studies evaluating the utility of the assay in node-positive patients, examines the impact of the assay results on treatment decisions, and discusses the health outcomes and health care expenditures associated with this assay.

GSK-3 inhibition overcomes chemoresistance in human breast cancer

Glycogen Synthase Kinase-3β (GSK-3β), a serine/threonine protein kinase, is an emerging therapeutic target in the treatment of human breast cancer. In this study, we demonstrate that the pharmacological inhibition of GSK-3 by two novel small molecule GSK-3 inhibitors, 9-ING-41 and 9-ING-87, reduced the viability of breast cancer cells but had little effect on non-tumorigenic cell growth. Moreover, treatment with 9-ING-41 enhanced the antitumor effect of irinotecan (CPT-11) against breast cancer cells in vitro. We next established two patient-derived xenograft tumor models (BC-1 and BC-2) from metastatic pleural effusions obtained from patients with progressive, chemorefractory breast cancer and demonstrated that 9-ING-41 also potentiated the effect of the chemotherapeutic drug CPT-11 in vivo, leading to regression of established BC-1 and BC-2 tumors in mice. Our results suggest that the inhibition of GSK-3 is a promising therapeutic approach to overcome chemoresistance in human breast cancer, and identify the GSK-3 inhibitor 9-ING-41 as a candidate targeted agent for metastatic breast cancer therapy.

Breast cancer and immunology: biomarker and therapeutic developments

While breast cancer has not historically been considered an immunogenic cancer, recent data demonstrating the powerful anti-cancer effects of immune checkpoints in many cancers, including breast cancer, has reinvigorated the field. Although the responses are generally low with single agents, some patients experience disease control for a long period of time. Selecting appropriate patients for immunotherapy is an important area of research, and many biomarkers are under investigation. Although immunotherapies are still in their early stages of development, learning how to use them in combination with other agents that can alter antigen presentation or other immune elements will be crucial. This review aims to summarize efforts in immune-related biomarker and drug development, particularly as it pertains to breast cancer.

Male Breast Cancer

Abstract Male breast cancer (MBC) is a rare disease, accounting for 1% of all breast cancers. Because of its rarity, it is treated similar to female breast cancer, although important differences exist. This chapter will address risk factors associated with MBC, clinical and pathologic features specific to MBC, and treatment and prognosis. Survivorship issues and surveillance recommendations unique to MBC will also be discussed.

Isolated Splenic Metastasis from Rectal Carcinoma: A Rare Occurrence

The presence of isolated splenic metastasis in rectal carcinoma is uncommon and usually presents as an asymptomatic mass, noted incidentally on imaging. Splenectomy is usually performed with the goal of curing metastatic disease. It is unclear if adjuvant chemotherapy affords any benefit, and the prognosis is unknown. The case of a young woman is reported, in whom an isolated metastatic lesion in the spleen was discovered 9 months after adjuvant chemotherapy for stage III rectal adenocarcinoma. The patient has remained disease-free for nearly 5 years following splenectomy and chemotherapy. To our knowledge, this is the fourth reported case in the English literature of an isolated splenic metastatic lesion from rectal cancer. We discuss the unique presentation, the importance of post-treatment surveillance, and the implementation of multi-modality treatment strategies in this young patient.

A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer

Immune checkpoint inhibitors produce modest responses in metastatic breast cancer, however, combination approaches may improve responses. A single arm pilot study was designed to determine the overall response rate (ORR) of durvalumab and tremelimumab, and evaluate immunogenomic dynamics in metastatic endocrine receptor (ER) positive or triple negative breast cancer (TNBC). Simon two-stage design indicated at least four responses from the first 18 patients were needed to proceed with the second stage. T-cell receptor (TCR) sequencing and immune-gene expression profiling were conducted at baseline and two months, whole exome sequencing was conducted at baseline. Eighteen evaluable patients were accrued (11 ER-positive; seven TNBC). Only three patients had a response (ORR = 17%), thus the study did not proceed to the second stage. Responses were only observed in patients with TNBC (ORR = 43%). Responders versus non-responders had upregulation of CD8, granzyme A, and perforin 1 gene expression, and higher mutational and neoantigen burden. Patients with TNBC had an oligoclonal shift of the most abundant TCR-beta clonotypes compared to those with ER-positive disease, p = 0.004. We conclude responses are low in unselected metastatic breast cancer, however, higher rates of clinical benefit were observed in TNBC. Immunogenomic dynamics may help identify phenotypes most likely to respond to immunotherapy.

High-Grade KIT-Negative Sarcoma of the Small Bowel in a Patient With Chronic Myeloid Leukemia Receiving Long-Term Tyrosine Kinase Inhibitors

Case Report A 65-year-old man with a history of hypertension, hypercholesterolemia, and peripheral vascular disease was diagnosed with chronic phase chronic myeloid leukemia (CML) in 1998. He was treated with interferon and cytarabine, which resulted in a complete cytogenetic remission. In August 2000, imatinib (Gleevec; Novartis, East Hanover, NJ) at a dose of 400 mg per day was started for cytogenetic relapse. Complete cytogenetic remission was achieved after 3 months of therapy. Ten years later, cytogenetic relapse reoccurred and imatinib dosing was increased to 800 mg, and then was discontinued shortly thereafter because of adverse effects. Therapy was changed to nilotinib (Tasigna; Novartis) at a dose of 400 mg twice per day. Eleven months later, the patient developed leg cramps and weakness that were attributed to nilotinib, which was discontinued and replaced with dasatinib (Sprycel; Bristol-Myers Squibb, Princeton, NJ) at a dose of 100 mg once per day. The patient experienced intermittent abdominal pain during the ensuing 4 months, which culminated in hospitalization for upper GI bleeding. Computed tomography (CT) enterography was performed and revealed an enhancing polypoid mass (Fig 1, arrow) at the duodenojejunal junction and retroperitoneal lymphadenopathy. Esophagogastroduodenoscopy demonstrated a medium-sized hemorrhagic mass in the third part of the duodenum. Endoscopic biopsy revealed a poorly differentiated high-grade malignancy of unknown origin, located mainly in the submucosa. Immunohistochemical staining was positive for vimentin and negative for epithelial and neuroendocrine markers, lymphoid, myeloid, melanoma, and endothelial markers. c-KIT and CDX2 staining were negative. Serum chromogranin-A (CgA) was 1.5 the upper limit of normal. Additional staging with positron emission tomography (PET)/CT revealed [F]fluorodeoxyglucose–avid small bowel foci associated with mass-like formations with standardized uptake values of 12 and 18.3. Confluent retroperitoneal hypermetabolic lymphadenopathy was noted with a maximum standardized uptake value of 19.8. In-111 pentetreotide scintigraphy (In-111 diethylenetriamine penta-acetic acid) with single-photon emission computed tomography–CT fusion was performed and demonstrated a focus of abnormal radiotracer uptake corresponding to the duodenal tumor. All of these findings suggested the possibility of a type IV neuroendocrine carcinoma of the small bowel. The patient was not deemed a resection candidate because of evidence of nonregional lymph node metastases. Dasatinib was discontinued and cisplatin and etoposide were initiated in June 2011 on the basis of the established regimen for metastatic high-grade neuroendocrine carcinoma. Abdominal pain and the need for transfusion support persisted after an initial modest improvement. Imaging to assess tumor response revealed progression of disease in all areas. Because of ongoing bleeding, the patient underwent palliative resection of the tumor. Intraoperative findings included an 8-cm tumor (spanning the mid-duodenum to the jejunum) with intraluminal and mesenteric extension, mesenteric vessel involvement, mesenteric lymphadenopathy, as well as liver metastases. Pathologic examination revealed a 13-cm high-grade malignant neoplasm (Fig 2A) that was composed of sheets of epithelioid cells with abundant eosinophilic cytoplasm, prominent nucleoli, high mitotic activity, and necrosis (Fig 2B, hematoxylin and eosin staining, 200 original magnification). By immunohistochemistry, the tumor demonstrated positivity for CD34 (scattered cells), vimentin (strongly diffuse), EMA (multifocal; Fig 2C, 400 original magnification), MNF-116 (scattered cells), CAM 5.2 (scattered cells; Fig 2D, 400 original magnification), whereas it was negative for INI-1 (retained; Fig 2E, 400 original magnification), ERG, desmin, DOG1.1, c-KIT, and lymphoid and melanoma markers. Immunostaining for plateletderived growth factor receptor alpha (PDGFRA) was equivocal. The final diagnosis was a malignant epithelioid cell neoplasm favoring high-grade sarcoma. One month postoperatively, the patient had follow-up CT imaging that revealed rapid progression of disease with new bilobar hepatic metastases, progressively enlarging lymphadenopathy, and new omental metastases. The patient decided on palliative hospice care in view of his debilitated state and rapid progression of disease. Additional polymerase chain reaction mutational analysis performed post hoc revealed deletion of KIT exon 11 (Fig 2F) and a concomitant KRAS G12V mutation. No mutations were found in KIT exons 13, 14, 17, BRAF (exon 15 tested), PDGFRA (exons 12 and 18) or p53. Fig 1. JOURNAL OF CLINICAL ONCOLOGY D I A G N O S I S I N O N C O L O G Y VOLUME 31 NUMBER 11 APRIL 1