Hank Schmidt

Breast Cancer in Male-to-Female Transsexuals: Use of Breast Imaging for Detection

OBJECTIVE The purposes of this article are to describe two cases of breast cancer in male-to-female transsexuals and to review eight cases previously reported in the literature. CONCLUSION Breast cancer occurs in male-to-female transsexuals who receive high doses of exogenous estrogen and develop breast tissue histologically identical to that of a biologically female breast. This exposure to estrogen results in increased risk of breast cancer. The first patient described is a male-to-female transsexual with screening-detected ductal carcinoma in situ and a family history of breast cancer. The other patient is a male-to-female transsexual with invasive ductal carcinoma that was occult on diagnostic digital mammographic and ultrasound findings but visualized on digital breast tomosynthesis and breast MR images. The analysis of the eight previously reported cases showed that breast cancer in male-to-female transsexuals occurs at a younger age and is more frequently estrogen receptor negative than breast cancer in others born biologically male. Screening for breast cancer in male-to-female transsexuals should be undertaken for those with additional risk factors (e.g., family history, BRCA2 mutation, Klinefelter syndrome) and should be available to those who desire screening, preferably in a clinical trial.

Lactation opposes pappalysin‐1‐driven pregnancy‐associated breast cancer

Pregnancy is associated with a transient increase in risk for breast cancer. However, the mechanism underlying pregnancy‐associated breast cancer (PABC) is poorly understood. Here, we identify the protease pappalysin‐1 (PAPP‐A) as a pregnancy‐dependent oncogene. Transgenic expression of PAPP‐A in the mouse mammary gland during pregnancy and involution promotes the deposition of collagen. We demonstrate that collagen facilitates the proteolysis of IGFBP‐4 and IGFBP‐5 by PAPP‐A, resulting in increased proliferative signaling during gestation and a delayed involution. However, while studying the effect of lactation, we found that although PAPP‐A transgenic mice lactating for an extended period of time do not develop mammary tumors, those that lactate for a short period develop mammary tumors characterized by a tumor‐associated collagen signature (TACS‐3). Mechanistically, we found that the protective effect of lactation is associated with the expression of inhibitors of PAPP‐A, STC1, and STC2. Collectively, these results identify PAPP‐A as a pregnancy‐dependent oncogene while also showing that extended lactation is protective against PAPP‐A‐mediated carcinogenesis. Our results offer the first mechanism that explains the link between breast cancer, pregnancy, and breastfeeding.

p53 Maintains Baseline Expression of Multiple Tumor Suppressor Genes.

TP53 is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes, including PTEN, STK11(LKB1), miR-34a, KDM6A(UTX), FOXO1, PHLDA3, and TNFRSF10B through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of TP53 associated with reduced expression of many of these genes. Regarding PTEN, p53 activated expression of a luciferase reporter gene containing the p53-consensus site in the PTEN enhancer, and homozygous deletion of this region in cells decreased PTEN expression and increased growth and transformation. These findings show that p53 maintains expression of a team of tumor suppressor genes that may together with the stress-induced targets mediate the ability of p53 to suppress cancer development. p53 mutations selected during tumor initiation and progression, thus, inactivate multiple tumor suppressor genes in parallel, which could account for the high frequency of p53 mutations in cancer. Implications: In this study, we investigate the activities of p53 under normal low-stress conditions and discover that p53 is capable of maintaining the expression of a group of important tumor suppressor genes at baseline, many of which are haploinsufficient, which could contribute to p53-mediated tumor suppression. Mol Cancer Res; 15(8); 1051–62. ©2017 AACR.

Optical Coherence Tomography: A Novel Imaging Method for Post-lumpectomy Breast Margin Assessment—A Multi-reader Study

RATIONALE AND OBJECTIVES This study aimed to assess whether different breast cancer subspecialty physicians can be trained to distinguish non-suspicious from suspicious areas of post-lumpectomy specimen margin in patients with breast cancer using optical coherence tomography (OCT) images (a near-infrared based imaging technique) with final histology as the reference standard. MATERIALS AND METHODS This institutional review board-exempt, Health Insurance Portability and Accountability Act-compliant study was performed on 63 surgically excised breast specimens from 35 female patients, creating a 90-case atlas containing both non-suspicious and suspicious areas for cancer. OCT images of the specimens were performed, providing 6.5-15 µm resolution with tissue visualization 1-2 mm subsurface. From the 90-case atlas, 40 cases were chosen for training and 40 were randomly selected for reader assessment. Three breast imaging radiologists, two pathologists, two breast surgeons, and one non-clinical reader were trained and assessed for ability to distinguish non-suspicious from suspicious findings blinded to clinical data and corresponding histology slides. Duration of training and assessment, sensitivity, specificity, positive predictive value, negative predictive value, and the area under the curve for each reader were calculated as well as averages by subspecialty. RESULTS The average training time was 3.4 hours (standard deviation, 1.2). The average assessment time was 1.9 hours (standard deviation, 0.7). The overall average reader sensitivity, specificity, and accuracy for detecting suspicious findings with histologic confirmation of cancer at the surgical margin for all eight readers were 80%, 87%, and 87%, respectively. Radiologists demonstrated the highest average among the disciplines, 85%, 93%, and 94%, followed by pathologists, 79%, 90%, and 84%, and surgeons, 76%, 84%, and 82% respectively. CONCLUSIONS With relatively short training (3.4 hours), readers from different medical specialties were able to distinguish suspicious from non-suspicious OCT imaging findings in ex vivo breast tissue as confirmed by histology. These results support the potential of OCT as a real-time intraoperative tool for post-lumpectomy specimen margin assessment.

Physician preference and patient satisfaction with radioactive seed versus wire localization

BACKGROUND Nonpalpable breast lesions require localization before excision. This is most commonly performed with a wire (WL) or a radioactive seed (SL), which is placed into the breast under radiographic guidance. Although there are advantages of each modality, there are no guidelines to address which patients should undergo WL versus SL. We investigated factors influencing the selection of SL versus WL at our institution and assessed patient satisfaction with each procedure. METHODS Patients undergoing preoperative localization of nonpalpable breast lesions from May 2014 through August 2015 were included. Physicians were surveyed on surgical scheduling to evaluate factors influencing the decision to perform SL or WL. Patient satisfaction was evaluated with a survey at the first postoperative visit. Retrospective chart review was performed. RESULTS 341 patients were included: 104 (30%) patients underwent SL and 237 (70%) underwent WL. There was no difference in patient age, benign versus malignant disease, or need for concomitant axillary surgery comparing the SL versus WL groups. Physician survey indicated that 18% of patients were candidates for WL only. Of the patients who were eligible for both, 88 (41%) ultimately underwent SL and 126 (59%) had WL. The most commonly cited reason for selection of one localization method or the other was physician preference, followed by patient preference or avoiding additional visit. There was no significant difference in self-reported preoperative anxiety level, convenience of the localization procedure, pain of the localization procedure, operative experience, postoperative pain level or medication requirement, or overall patient satisfaction comparing patients who underwent SL and WL. CONCLUSIONS SL and WL offer patients similar comfort and satisfaction. Factors influencing selection of one modality over the other include both logistic and clinical considerations.

Utility of surveillance MRI in women with a personal history of breast cancer

PURPOSE To determine the utility and rate of biopsy in women with a positive history of breast cancer screened with MRI. METHODS Retrospective review of 491 breast MRI screening examinations in women with a personal history of breast cancer. RESULTS In total, 107 biopsies were performed, an average of 0.09 biopsies per person year. The positive predictive value for biopsies prompted by MRI findings was 0.24 (95% C.I. 0.10-0.38). Eight of the nine subsequent cancers were initially identified on screening MRI alone. CONCLUSION Surveillance MRI in breast cancer survivors may increase detection of subsequent cancers while increasing rate of biopsy.

Patient-derived Interstitial Fluids and Predisposition to Aggressive Sporadic Breast Cancer through Collagen Remodeling and Inactivation of p53

Purpose: Despite the fact that interstitial fluid (IF) represents a third of our body fluid, it is the most poorly understood body fluid in medicine. Increased IF pressure is thought to result from the increased deposition of extracellular matrix in the affected tissue preventing its reabsorption. In the cancer field, increased rigidity surrounding a cancerous mass remains the main reason that palpation and radiologic examination, such as mammography, are used for cancer detection. While the pressure produced by IF has been considered, the biochemical composition of IF has not been considered in its effect on tumors. Experimental Design: We classified 135 IF samples from bilateral mastectomy patients based on their ability to promote the invasion of breast cancer cells. Results: We observed a wide range of invasion scores. Patients with high-grade primary tumors at diagnosis had higher IF invasion scores. In mice, injections of high-score IF (IFHigh) in a normal mammary gland promotes ductal hyperplasia, increased collagen deposition, and local invasion. In a mouse model of residual disease, IFHigh increased disease progression and promoted aggressive visceral metastases. Mechanistically, we found that IFHigh induces myofibroblast differentiation and collagen production through activation of CLIC4. IFHigh also downregulates RYBP, leading to degradation of p53. Furthermore, in mammary glands of heterozygous p53-mutant knock-in mice, IFHigh promotes spontaneous tumor formation. Conclusions: Our study indicates that IF can increase the deposition of extracellular matrix and raises the provocative possibility that they play an active role in the predisposition, development, and clinical course of sporadic breast cancers. Clin Cancer Res; 23(18); 5446–59. ©2017 AACR.

A unique presentation of occult primary breast cancer with a review of the literature.

We are reporting a case of a 34-year-old woman with occult primary breast cancer discovered after initially presenting with neurological symptoms. She was successfully treated with neoadjuvant chemotherapy followed by definitive axillary lymph node dissection and ipsilateral whole breast radiotherapy. The case presented is unique due to the rarity of occult primary breast cancer, especially in light of her initial confounding neurological signs and symptoms, which highlights the importance of careful staging.

Mouse ER+/PIK3CAH1047R breast cancers caused by exogenous estrogen are heterogeneously dependent on estrogen and undergo BIM-dependent apoptosis with BH3 and PI3K agents

Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R−induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER−independent PIK3CA-mutant breast cancer.

Metastatic Carcinoid Tumor Presenting as a Breast Mass: A Case Report and Review of the Literature

Carcinoid tumors are indolent neoplasms derived from the enterochromaffin cells which have a wide anatomic distribution. Most common primary sites include gastrointestinal tract and bronchopulmonary system. Despite their slow growing nature, carcinoid tumors possess metastatic potential, and breast is a rare but known site of metastasis. We report a case of breast metastasis from carcinoid tumor of the terminal ileum in a 53 year old woman who initially presented with a breast mass detected by screening mammography. A review of literature was performed for this rare presentation of breast as the initial site of detection of metastatic carcinoid tumor.