HER2 testing in breast cancers: comparison of assays and interpretation using ASCO/CAP 2013 and 2018 guidelines.

PURPOSE: HER2 overexpression and gene amplification are routinely tested by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. In addition, HER2 mRNA expression is also tested by the Oncotype DX assay. Discordance between laboratories among the different assays remains a problem. To improve the routine HER2 reporting, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) updated their guidelines in 2018. Our study will compare concordance of HER2 status by IHC and FISH using ASCO/CAP 2013 and 2018 guidelines with Oncotype DX. METHODS: We retrospectively reviewed 657 estrogen receptor positive primary breast cancer cases with available Oncotype DX tests between 2011 and 2018. Medical records were reviewed for HER2 results by IHC, FISH, and Oncotype DX. The HER2 results by different assays and between 2013 and 2018 guidelines were compared. RESULTS: Of the 657 cases, 280 were tested by IHC, FISH, and Oncotype DX. HER2-equivocal cases by IHC 2013 guidelines were all negative (67/67, 100%) by FISH 2018 guidelines and by Oncotype DX. HER2-equivocal cases by FISH 2013 guidelines were all negative (16/16, 100%) by FISH 2018 guidelines, while 15/16 (93.8%) negative and 1/16 (6.2%) equivocal by Oncotype DX. The HER2-equivocal and HER2-negative groups were similar in age, gender, histology, grade, and Ki67 score. CONCLUSIONS: HER2 concordance was highest between Oncotype DX (99.6%) and FISH per 2018 guidelines. This suggests that the ASCO/CAP 2018 guidelines improved the accurate stratification of HER2-equivocal cases.

Correction to: The Emerging Roles of Steroid Hormone Receptors in Ductal Carcinoma in Situ (DCIS) of the Breast.

The original version of this article unfortunately contained mistakes.

The Emerging Roles of Steroid Hormone Receptors in Ductal Carcinoma in Situ (DCIS) of the Breast.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor to most types of invasive breast cancer (IBC). Although it is estimated only one third of untreated patients with DCIS will progress to IBC, standard of care for treatment is surgery and radiation. This therapeutic approach combined with a lack of reliable biomarker panels to predict DCIS progression is a major clinical problem. DCIS shares the same molecular subtypes as IBC including estrogen receptor (ER) and progesterone receptor (PR) positive luminal subtypes, which encompass the majority (60-70%) of DCIS. Compared to the established roles of ER and PR in luminal IBC, much less is known about the roles and mechanism of action of estrogen (E2) and progesterone (P4) and their cognate receptors in the development and progression of DCIS. This is an underexplored area of research due in part to a paucity of suitable experimental models of ER+/PR + DCIS. This review summarizes information from clinical and observational studies on steroid hormones as breast cancer risk factors and ER and PR as biomarkers in DCIS. Lastly, we discuss emerging experimental models of ER+/PR+ DCIS.

Targeting the Pro-survival Protein BCL-2 to Prevent Breast Cancer.

Current chemopreventive strategies require 3-5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone receptor. Venetoclax is a BH3 mimetic that blocks the anti-apoptotic protein BCL-2 and has efficacy in treating breast cancer. We found that venetoclax treatment of atypia-bearing mice delayed the progression to tumors, improved overall survival, and reduced pulmonary metastasis. Therefore, prophylactic treatment to inhibit the pro-survival protein BCL-2 may provide an alternative to the currently available regimens in breast cancer prevention. PREVENTION RELEVANCE: This study demonstrates that prophylactic treatment with the BCL2-specific antagonist venetoclax prevents breast cancer initiated by a mutated and activated PIK3CA, the most common breast oncogene.

Pathologic findings in women with atypical glandular cells on Pap test.

INTRODUCTION: It has been shown that a significant subset of atypical glandular cells (AGC) indicates underlying malignancies. Therefore, it is imperative to recognize, diagnose, and treat these lesions early. We evaluated the clinical significance of AGC on cervical cytology in our hospital. MATERIALS AND METHODS: A total of 376 consecutive Pap tests with a diagnosis of AGC between January 2005 and January 2011 at a tertiary community hospital were reviewed and correlated with concurrent or follow-up histopathology. RESULTS: Over a 6-year period 376 (0.23%) Pap tests were reported as AGC. Histopathology was available in 223 cases. Atypical hyperplasia, dysplasia, or malignant lesion was found in 128 (57.4%) cases. Of these, 80 (62.5%) were glandular lesions. In women younger than 48 years benign lesions (52.9%) were more common. Women who were 48 years and older were more likely to have a malignant glandular lesion (56 out of 73, 76.7%) compared with women under 48 years, who were more likely to have a malignant squamous lesion (31 out of 55, 56.4%).This difference was statistically significant (P = 0.002). Malignant lesion was seen in 58 (26%) of the women. Endometrial carcinoma (30 cases) was the most common malignancy-51.7% of the malignant lesions and 13.4% overall. Chronic cervicitis and endometritis were the most common non-malignant findings. CONCLUSION: AGC on Pap test may be the initial manifestation of a wide range of cervical pathologies. Because many AGC diagnoses did not have a histopathological follow-up, clinicans should be more diligent at having patients follow up, especially in peri- and post-menopausal women.

Clear cell sarcoma of kidney: morphoproteomic analysis reveals genomic correlates and therapeutic options.

We used the morphoproteomic approach to analyze clear cell sarcoma of kidney (CCSK), a rare pediatric renal tumor, for which the exact pathogenesis and reliable diagnostic markers remain inexplicable. The tumor, currently being treated with chemotherapy and radiation therapy before or after radical nephrectomy, has demonstrated improved survival rates after introduction of doxorubicin. Three cases of CCSK were studied. We attempted to decipher the possible pathological mechanisms involved in CCSK and to explore the therapeutic targets and plausible less-toxic chemotherapeutic agents. We propose that cyclin D1 may be a central molecule in the pathogenesis of CCSK, driven mainly by the sonic hedgehog and the nuclear factor-kappa B pathways and secondarily by the mammalian target of rapamycin complex mTORC2/PI3K/Akt pathway, heat shock protein 90, and possibly phospholipase D1. Inclusion of relatively less toxic but effective therapies in the form of statins, 13-cis retinoic acid, curcumin, and 17-AAG in the combinatorial treatment strategies, which can target the involved subcellular pathways, may be considered.

Anemia and jejunal intussusception: An unusual presentation for a metastatic phyllodes breast tumor.

INTRODUCTION: Phyllodes tumor of the breast is a rare cause of breast cancer, accounting for less than 0.5% of breast cancers. These tumors are classified as benign, borderline, or malignant, with malignant tumors compromising nearly 25% of cases. Metastases occur in 20% of malignant tumors, lungs, bones, liver and brain being the frequent sites of metastases. PRESENTATION OF CASE: We present a case of a metastatic phyllodes tumor to the small bowel causing jejunal intussusception, symptomatic anemia, and small bowel obstruction. DISCUSSION: Patients with phyllodes tumor of the breast can develop disease recurrence even years after initial treatment. Phyllodes tumor metastasizing to the small bowel is extremely rare, with only three known previously described case reports in the literature. CONCLUSION: High risk patients, with a past medical history of phyllodes breast cancer, should be monitored closely. Even years after breast cancer treatment, these patients may present with gastrointestinal complaints such as obstruction or bleeding, and therefore metastatic disease to the small bowel should be considered on the differential with subsequent abdominal imaging obtained.

Leiomyosarcoma of the renal pelvis.

Leiomyosarcomas are rare malignant tumors of the kidney. They may arise from the renal capsule, renal vein, renal pelvic musculature or renal parenchyma. Renal pelvis is an uncommon site of occurrence, with around 10 cases reported in the literature so far. Here we present a 60-year-old male who presented with increased urinary frequency, lower limb weakness, anorexia and weight loss. Imaging showed a right renal mass. A renal cell carcinoma was suspected clinically. A right nephrectomy was performed, which showed a large circumscribed mass in the hilar region. Histology revealed a tumor mass arising from the renal pelvis. The tumor was composed of spindle cells arranged in fascicles. Immunohistochemistry showed tumor cells to be positive for smooth muscle actin (SMA) and desmin (Des) and negative for cytokeratin (CK), HMB 45, CD117 (C-kit), and CD34. That confirmed the diagnosis of leiomyosarcoma.