Tari A. King

Tumour exosome integrins determine organotropic metastasis.

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

ESR1 ligand-binding domain mutations in hormone-resistant breast cancer

Seventy percent of breast cancers express estrogen receptor (ER), and most of these are sensitive to ER inhibition. However, many such tumors for unknown reasons become refractory to inhibition of estrogen action in the metastatic setting. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases. These included highly recurrent mutations encoding p.Tyr537Ser, p.Tyr537Asn and p.Asp538Gly alterations. Molecular dynamics simulations suggest that the structures of the Tyr537Ser and Asp538Gly mutants involve hydrogen bonding of the mutant amino acids with Asp351, thus favoring the agonist conformation of the receptor. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists. These data implicate LBD-mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may be of substantial therapeutic benefit.

Long-term results of wide-field brachytherapy as the sole method of radiation therapy after segmental mastectomy for Tis,1,2 breast cancer

BACKGROUND We hypothesized that wide-field brachytherapy (BRT) after margin negative excision would result in complication rates, local recurrence rates, and cosmesis scores equivalent to external beam radiotherapy (ERT). METHODS Patients with T(is,1,2) tumors less than or equal to 4 cm, 0 to 3 positive axillary nodes, and negative inked surgical margins were entered prospectively into BRT phase I/II trial. Patients who met the eligibility criteria for BRT but were treated with ERT during the same time period were retrospectively identified as controls. A blinded panel of healthcare professionals graded cosmetic outcome. RESULTS Fifty patients with 51 breast cancers received BRT from January 1992 to October 1993. We identified 94 patients eligible for BRT but concurrently treated with ERT. At a median follow-up of 75 months, the two groups were similar for grade III treatment toxicities, local/regional recurrence rates, and cosmesis scores. CONCLUSIONS For selected breast cancer patients undergoing breast-conserving therapy, BRT is an attractive alternative to ERT.

Tumor Entrained Neutrophils Inhibit Seeding in the Premetastatic Lung

Primary tumors have been shown to prepare distal organs for later colonization of metastatic cells by stimulating organ-specific infiltration of bone marrow derived cells. Here we demonstrate that neutrophils accumulate in the lung prior to the arrival of metastatic cells in mouse models of breast cancer. Tumor-entrained neutrophils (TENs) inhibit metastatic seeding in the lungs by generating H(2)O(2) and tumor secreted CCL2 is a critical mediator of optimal antimetastatic entrainment of G-CSF-stimulated neutrophils. TENs are present in the peripheral blood of breast cancer patients prior to surgical resection but not in healthy individuals. Thus, whereas tumor-secreted factors contribute to tumor progression at the primary site, they concomitantly induce a neutrophil-mediated inhibitory process at the metastatic site.

Clinical Management Factors Contribute to the Decision for Contralateral Prophylactic Mastectomy

PURPOSE To determine whether increasing rates of contralateral prophylactic mastectomy (CPM) are due to recognition of risk factors for contralateral breast cancer (CBC) or treatment factors related to the index lesion. METHODS From 1997 to 2005, 2,965 patients with stage 0 to III primary unilateral breast cancer underwent mastectomy at Memorial Sloan-Kettering Cancer Center. Patients who did and did not undergo CPM within 1 year of treatment for their index cancer were compared to identify independent predictors of CPM. RESULTS The rate of CPM was 13.8% (n = 407), increasing from 6.7% in 1997 to 24.2% in 2005 (P < .0001). Patients with BRCA mutations or prior mantle radiation (n = 52) accounted for 13% of those having CPM. The rate of CPM by surgeon varied from 1% to 26%. Multivariate logistic regression adjusting for surgeon-identified white race (odds ratio [OR] = 3.3), immediate reconstruction (OR = 3.3), family history of breast cancer (OR = 2.9), magnetic resonance imaging (MRI) at diagnosis (OR = 2.8), age younger than 50 years (OR = 2.2), noninvasive histology (OR = 1.8), and prior attempt at breast conversation (OR = 1.7) to be independent predictors of CPM. CONCLUSION These data suggest that increasing use of CPM is not associated with increased recognition of patients at high risk for CBC. Treatment factors, such as immediate reconstruction, preoperative MRI, and unsuccessful attempts at breast conservation, are associated with increased rates of CPM. Efforts to optimize breast conservation, minimize unnecessary tests, and improve patient education about the low risk of CBC may help to curb this trend.

Measuring Quality of Life in Oncologic Breast Surgery: A Systematic Review of Patient‐Reported Outcome Measures

Abstract:  Multiple randomized trials demonstrate equivalent survival between BCT and mastectomy, but clinical outcomes research must also evaluate patient satisfaction and quality of life. This review analyzes existing patient‐reported outcome (PRO) measures in oncologic breast surgery to assess utility and make recommendations for future research. We performed a systematic literature review to identify PRO measures used in oncologic breast surgery patients. After applying inclusion and exclusion criteria, qualifying instruments were assessed for adherence to international guidelines for health outcomes instrument development and validation. Ten measures underwent development and psychometric evaluation in an oncologic breast surgery population. Five of ten measures (EORTC QLQ BR‐23, FACT‐B, HBIS, BIBCQ, and BREAST‐Q) reported an adequate development and validation process. Three of these 5 measures (EORTC QLQ BR‐23, FACT‐B, HBIS) focused on non‐surgical treatment issues. A fourth instrument (BIBCQ) did not address aesthetic concerns after breast reconstruction. The fifth instrument (BREAST‐Q) was developed for use in patients undergoing mastectomy ± reconstruction, but did not address breast‐conserving therapy. Overall, two key limitations were noted: 1) surgery‐specific issues of breast‐conserving surgery patients were not well represented and 2) measures were largely developed without the aid of newer psychometric methods that may improve their clinical utility. Reliable and valid PRO measures in breast cancer patients exist, but even the best instruments do not address all important surgery‐specific and psychometric issues of oncologic breast surgery patients. Newer psychometric methods would facilitate development of scales for use in individual patient care as well as group level comparisons.

Frequent Mutational Activation of the PI3K-AKT Pathway in Trastuzumab-Resistant Breast Cancer

Purpose: HER2-amplified breast cancer is sometimes clinically insensitive to HER2-targeted treatment with trastuzumab. Laboratory models of resistance have causally implicated changes in HER2 expression and activation of the phosphoinositide 3-kinase (PI3K)–AKT pathway. We conducted a prospective tissue acquisition study to determine if there is evidence for these lesions in metastatic tumors that have progressed on trastuzumab-containing therapy. Experimental Design: From 2/2007 to 11/2011, 63 patients with HER2-amplified breast cancer with recurrence of disease after adjuvant trastuzumab therapy or World Health Organization–defined progression of metastatic disease on a trastuzumab-containing regimen were prospectively enrolled and underwent tumor biopsy. Specimens were analyzed for activating mutations in PIK3CA and HER2 by Sequenom and analyzed for HER2 and PTEN status by immunohistochemistry. Results: In 53/60 cases (88%, 3 cases not evaluable for HER2), HER2 overexpression persisted in the metastatic tumor following trastuzumab exposure. Among the 7 cases lacking HER2 overexpression, repeat analysis of the pretreatment tumor failed to confirm HER2 overexpression in five cases. Among cases evaluable for PTEN (56) or PI3K mutation (45), absent or significantly diminished PTEN expression was noted in 33 (59%) and activating mutations in PIK3CA in 13 (29%). The combined rate of PTEN loss and PIK3CA mutation in the trastuzumab-refractory tumors was 71% compared with 44% (P = 0.007) in an unexposed cohort of 73 HER2-amplified tumors. Conclusions: In this series of prospectively collected trastuzumab-refractory human breast cancers, loss of HER2 overexpression was rare, whereas activation of the PI3K-AKT pathway through loss of PTEN or PIK3CA mutation was frequently observed. Clin Cancer Res; 18(24); 6784–91. ©2012 AACR.

Stage IV breast cancer in the era of targeted therapy: does surgery of the primary tumor matter?

Multiple studies have suggested that resection of the primary tumor improves survival in patients with stage IV breast cancer, yet in the era of targeted therapy, the relation between surgery and tumor molecular subtype is unknown. The objective of the current study was to identify subsets of patients who may benefit from primary tumor treatment and assess the frequency of local disease progression.

Progression from ductal carcinoma in situ to invasive breast cancer: Revisited

Ductal carcinoma in situ (DCIS) is an intraductal neoplastic proliferation of epithelial cells that is separated from the breast stroma by an intact layer of basement membrane and myoepithelial cells. DCIS is a non‐obligate precursor of invasive breast cancer, and up to 40% of these lesions progress to invasive disease if untreated. Currently, it is not possible to predict accurately which DCIS would be more likely to progress to invasive breast cancer as neither the significant drivers of the invasive transition have been identified, nor has the clinical utility of tests predicting the likelihood of progression been demonstrated. Although molecular studies have shown that qualitatively, synchronous DCIS and invasive breast cancers are remarkably similar, there is burgeoning evidence to demonstrate that intra‐tumor genetic heterogeneity is observed in a subset of DCIS, and that the process of progression to invasive disease may constitute an ‘evolutionary bottleneck’, resulting in the selection of subsets of tumor cells with specific genetic and/or epigenetic aberrations. Here we review the clinical challenge posed by DCIS, the contribution of the microenvironment and genetic aberrations to the progression from in situ to invasive breast cancer, the emerging evidence of the impact of intra‐tumor genetic heterogeneity on this process, and strategies to combat this heterogeneity.

Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis.

BackgroundFor individuals genetically predisposed to breast and ovarian cancer through inheritance of a mutant BRCA allele, somatic loss of heterozygosity affecting the wild-type allele is considered obligatory for cancer initiation and/or progression. However, several lines of evidence suggest that phenotypic effects may result from BRCA haploinsufficiency.MethodsArchival fixed and embedded tissue specimens from women with germ line deleterious mutations in BRCA1 or BRCA2 were identified. After pathologic review, focal areas of normal breast epithelium, atypical ductal hyperplasia, ductal carcinoma-in-situ, and invasive ductal carcinoma were identified from 14 BRCA1-linked and 9 BRCA2-linked breast cancers. Ten BRCA-linked prophylactic mastectomy specimens and 12 BRCA-linked invasive ovarian carcinomas were also studied. Laser catapult microdissection was used to isolate cells from the various pathologic lesions and corresponding normal tissues. After DNA isolation, real-time polymerase chain reaction assays were used to quantitate the proportion of wild-type to mutant BRCA alleles in each tissue sample.ResultsQuantitative allelotyping of microdissected cells revealed a high level of heterogeneity in loss of heterozygosity within and between preinvasive lesions and invasive cancers from BRCA1 and BRCA2 heterozygotes with breast cancer. In contrast, all BRCA-associated ovarian cancers displayed complete loss of the wild-type BRCA allele.ConclusionsThese data suggest that loss of the wild-type BRCA allele is not required for BRCA-linked breast tumorigenesis, which would have important implications for the genetic mechanism of BRCA tumor suppression and for the clinical management of this patient population.