Adriana D. Corben

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions.

Introduction: Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors. Areas covered: The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents. Expert opinion: The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance.

The epichaperome is an integrated chaperome network that facilitates tumour survival

Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes—dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically ‘rewired’ to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.

Non-mammary metastases to the breast and axilla: a study of 85 cases

Non-mammary metastases to the breast and axilla are rare occurrences. However, they are important diagnostic considerations as their treatment and prognosis differ significantly from primary breast cancer. Between 1990 and 2010, we identified a total of 85 patients, 72 women and 13 men, with non-mammary malignancies involving the breast, axilla, or both. The tumor types consisted of carcinoma (58%), melanoma (22%) and sarcoma (20%). Ovary was the most common site of origin for carcinoma, and metastatic high-grade ovarian serous carcinoma was most frequently misdiagnosed as a primary breast carcinoma. Melanoma was the single most common non-carcinomatous tumor type to involve the breast and/or axilla, and uterine leiomyosarcoma was the most common type of sarcoma. Most patients (77%) had other metastases at the time of diagnosis of the tumor, but in 11% the breast or axillary lesion was the first presentation. Without a clinical history, non-mammary metastases were difficult to diagnose because the majority of cases presented with a solitary nodule and lacked pathognomonic pathologic features. There were, however, certain recurrent histological findings identified, such as the often relatively well-circumscribed growth pattern of the metastatic lesion surrounded by a fibrous pseudocapsule, and the absence of an in situ carcinoma. Overall, these patients had poor survival; 96% of patients with follow-up available are dead of disease, with a median survival of 15 months after the diagnosis of the breast or axillary lesion. This finding emphasizes the need to accurately identify these tumors as metastases in order to avoid unnecessary procedures and treatments in these patients.

Detection of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer Using 89Zr-Trastuzumab PET/CT

Our objective was to determine whether imaging with a human epidermal growth factor receptor 2 (HER2)–targeted PET tracer can detect HER2-positive metastases in patients with HER2-negative primary breast cancer. Methods: Patients with HER2-negative primary breast cancer and evidence of distant metastases were enrolled in an Institutional Review Board–approved prospective clinical trial. Archived pathologic samples from the patient’s primary breast cancer were retested to confirm HER2-negative disease. Patients with confirmed HER2-negative primary breast cancer underwent 89Zr-trastuzumab PET/CT to screen for 89Zr-trastuzumab metastases. Metastases avid for 89Zr-trastuzumab by PET/CT were biopsied and pathologically examined to define HER2 status. Patients with pathologically proven HER2-positive metastases subsequently received off-protocol HER2-targeted therapy to evaluate treatment response. Results: Nine patients were enrolled, all of whom had pathologic retesting that confirmed HER2-negative primary breast cancer. Five demonstrated suggestive foci on 89Zr-trastuzumab PET/CT. Of these 5 patients, 2 had biopsy-proven HER2-positive metastases and went on to benefit from HER2-targeted therapy. In the other 3 patients, biopsy showed no evidence of HER2-positive disease, and their foci on 89Zr-trastuzumab PET were considered false-positive. Conclusion: In this proof-of-concept study, we demonstrated that 89Zr-trastuzmab PET/CT detects unsuspected HER2-positive metastases in patients with HER2-negative primary breast cancer. Although these are only initial results in a small sample, they are a proof of the concept that HER2-targeted imaging can identify additional candidates for HER2-targeted therapy. More specific HER2-targeted agents will be needed for clinical use.

Endosalpingiosis in Axillary Lymph Nodes: A Possible Pitfall in the Staging of Patients With Breast Carcinoma

The occurrence of benign epithelial inclusions in lymph nodes is well documented and can sometimes mimic metastatic carcinoma. Benign müllerian inclusions, such as endometriosis and endosalpingiosis, are common in pelvic and para-aortic lymph nodes, but their presence in supradiaphragmatic lymph nodes is a rare event. We report our experience with 3 patients found to have endosalpingiosis in axillary sentinel lymph nodes obtained for staging of breast carcinoma. All patients were postmenopausal women, with age ranging between 65 and 75 years. Endosalpingiosis involved a single lymph node in 1 patient, and 2 nodes in each of the other 2; it was present in the lymph node capsule in all the 3 cases, with few glands scattered within the lymph node parenchyma in 2 of the patients. The glands contained ciliated and intercalated peg cells, had no periglandular endometrial-type stroma, and showed no atypia or mitotic activity. The epithelium demonstrated positive nuclear immunoreactivity for WT1 and PAX8, and was devoid of myoepithelium or basement membrane. Endosalpingiosis had been misinterpreted as metastatic carcinoma at another hospital in 1 of the 3 patients, with subsequent dissection of 19 additional benign axillary lymph nodes. We conclude that endosalpingiosis can involve axillary lymph nodes and closely simulate metastatic mammary carcinoma. Morphologic identification of ciliated cells and “peg” cells is most helpful to recognize this benign inclusion, and positive immunoreactivity for WT1 and/or PAX8 can be used to support the diagnosis.

Appearance of untreated bone metastases from breast cancer on FDG PET/CT: importance of histologic subtype

PurposeTo determine if the histology of a breast malignancy influences the appearance of untreated osseous metastases on FDG PET/CT.MethodsThis retrospective study was performed under IRB waiver. Our Hospital Information System was screened for breast cancer patients who presented with osseous metastases, who underwent FDG PET/CT prior to systemic therapy or radiotherapy from 2009 to 2012. Patients with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), or mixed ductal/lobular (MDL) histology were included. Patients with a history of other malignancies were excluded. PET/CT was evaluated, blinded to histology, to classify osseous metastases on a per-patient basis as sclerotic, lytic, mixed lytic/sclerotic, or occult on CT, and to record SUVmax for osseous metastases on PET.ResultsFollowing screening, 95 patients who met the inclusion criteria (74 IDC, 13 ILC, and 8 MDL) were included. ILC osseous metastases were more commonly sclerotic and demonstrated lower SUVmax than IDC metastases. In all IDC and MDL patients with osseous metastases, at least one was FDG-avid. For ILC, all patients with lytic or mixed osseous metastases demonstrated at least one FDG-avid metastasis; however, in only three of seven patients were sclerotic osseous metastases apparent on FDG PET.ConclusionThe histologic subtype of breast cancer affects the appearance of untreated osseous metastases on FDG PET/CT. In particular, non-FDG-avid sclerotic osseous metastases were more common in patients with ILC than in patients with IDC. Breast cancer histology should be considered when interpreting non-FDG-avid sclerotic osseous lesions on PET/CT, which may be more suspicious for metastases (rather than benign lesions) in patients with ILC.

Lobular Carcinoma, Not Only a Classic

Abstract:  Lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia are rare lesions, found incidentally in breast biopsies. They have been regarded traditionally as high‐risk lesions, but recent genetic evidence and follow‐up data indicates that they also constitute nonobligate precursors of invasive carcinoma. In addition to 16q deletion, a genetic alteration common across the spectrum of low‐grade mammary epithelial neoplasia, lobular lesions consistently demonstrate deletion or functional inactivation of the CDH1/E‐cadherin gene, with consequent loss of membranous immunoreactivity for the same antigen. The use of E‐cadherin in the evaluation of solid mammary carcinoma in situ with ambiguous morphology has identified variants of LCIS characterized by massive acinar expansion and necrosis with calcifications, and/or marked nuclear pleomorphism or signet ring cell formation. In contrast to classic LCIS, these rare lesions are detected mammographically and often occur in association with invasive carcinoma. Genetic analysis of these tumors has confirmed lobular lineage and demonstrated more extensive chromosomal alterations than in classic LCIS. A pleomorphic variant of invasive lobular carcinoma has also been described. Here, we summarize our evolving knowledge of in situ and invasive lobular neoplasia and highlight the implications for patient management.

Radial Scar at Image-guided Needle Biopsy: Is Excision Necessary?

Optimal management of a lesion yielding radial scar (RS) without epithelial atypia on breast biopsy is controversial. In this single-institution study spanning 17 years, 53 patients with this biopsy diagnosis were evaluated in terms of clinical, radiologic, and pathologic features and outcomes. RSs were categorized as either “incidental” or as the “targeted” lesion according to defined criteria. Of 48 patients who underwent surgical excision after a diagnosis of RS on biopsy, only 1 had an “upgrade” diagnosis of malignancy (2%). No “incidental” RS was associated with the presence of malignancy on surgical excision. Meta-analysis of 20 RS excision studies demonstrated an overall upgrade rate of 10.4%, with a higher rate in patients with a diagnosis of RS with atypia (26%). The upgrade rate for RS without atypia was 7.5% overall. The lower rate of upgrade to malignancy in this study (2%) is likely related to the thorough radiologic-pathologic review undertaken. In the setting of multidisciplinary agreement and careful radiologic-pathologic correlation, it may be appropriate for patients with a biopsy diagnosis of RS without atypia to forego surgical excision in favor of imaging follow-up.

Breast intraductal papillomas without atypia in radiologic‐pathologic concordant core‐needle biopsies: Rate of upgrade to carcinoma at excision

The surgical management of mammary intraductal papilloma without atypia (IDP) identified at core‐needle biopsy (CNB) is controversial. This study assessed the rate of upgrade to carcinoma at surgical excision (EXC).

Management of breast cancer during pregnancy

INTRODUCTION Pregnancy-associated breast cancer (PABC) is one of the most common malignancies during pregnancy. Since maternal age at the time of pregnancy is increasing, PABC rate is expected to increase. Diagnostic delays are common. METHODS Retrospective observational study analysing twelve pregnant patients with breast cancer who underwent surgical treatment during the period of February 2006 to June 2013 at the Department of Surgery I, University of Insubria Varese. RESULTS The median age of pregnant patients was 34 y (range 28-44 y). Three patients were affected by BRCA1 mutation. In six patients diagnosis was made during gestation, in the other six patients breast cancer was discovered during breastfeeding. Ten patients underwent breast-conserving surgery. Sentinel lymph node biopsy was performed in six patients; in one of them it was positive so axillary dissection was simultaneuosly performed. Six patients underwent axillary dissection ab initio. In all cases the histological type was invasive ductal carcinoma; grade 3 in ten patients and grade 2 in two patients. Eleven of twelve patients received adjuvant chemotherapy, one patient both adjuvant and neoadjuvant. In three cases also radiation therapy was performed after delivery. In all cases healthy babies were born. Nine of twelve patients are still alive and disease free, after a median follow-up of 20 months (range 3-52 months). Three patients died from systemic progression of the disease. CONCLUSION There are no significant series of patients in worldwide literature to develop standard protocols. Pregnant women must be followed by a multidisciplinary team.