Citations

Increasing data support the importance of preexisting host immune response and neoantigen burden for determining response to immune checkpoint inhibitors (ICIs). In lung cancer and melanoma, tumor mutational burden (TMB) has emerged as an independent biomarker for ICI response. However, the significance of TMB in breast cancer, particularly in the context of PD-L1 negativity, remains unclear. This report describes a patient with HER2-negative breast cancer with high TMB and an apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) trinucleotide signature; her disease was refractory to multiple lines of treatments but achieved durable complete response using ICIs and capecitabine. Additional analysis of the tumor revealed a low amount of stromal tumor-infiltrating lymphocytes (sTILs) and PD-L1 negativity, reflecting a poor preexisting host immune response. In collaboration with Foundation Medicine, comprehensive genomic profiling from 14,867 patients with breast cancer with the FoundationOne test was evaluated. Using the cutoff of ≥10 mutations/megabase (mut/Mb) for high TMB, PD-L1 positivity and TMB-high populations were not significantly overlapping (odds ratio, 1.02;P=.87). Up to 79% of TMB-high tumors with >20 mut/Mb were PD-L1–negative. Our study highlights that despite having low TILs and PD-L1 negativity, some patients may still experience response to ICIs.

1059 Background: Relapsed TNBC is characterized by its poor prognosis. B is a synthetic DNA minor groove binding non-cross resistant agent that is fully active against DNA-mismatch repair deficient tumor cells. C increases GSH/GST in which enhances the efficacy of B. Methods: Phase II study in pts with mTNBC. C Day 1 followed by B Day 2, repeated every 21 days. Aim: Efficacy of C + B in mTNBC. Primary endpoint: PFS at 3 mo. Secondary endpoints include ORR, duration of response (DOR), 6-mo PFS, OS and AE profile. Tertiary endpoints include assessment of baseline GSH levels, prevalence of BCRA1 mutation and pERK, and correlations with outcome. Results: Closed 3/2012. 48 pts accrued (1 ineligible pt). Median f/u 11.4 mo (6.6-14.8); 2 pts still on treatment. 47 pts evaluable for the PFS endpoint and AEs. 49% received therapy as 3rd-5th line. Median number of cycles = 4 (range 1-15). There are currently 9 confirmed responses (8 PR and 1 CR); DOR = 2.6-14.5 mo. The 3-mo PFS = 51%; 6-mo PFS = 28%; the median TTP is 3.2 mo. AE data: 75% G3/4 hematologic AE: febrile neutropenia 19%. Non-hematologic AEs included G3 (47%) and G4 (15%): G3 fatigue 17%; and no G5 non-heme AE. No correlation of GSH/GST levels with outcome was found. Among 35 pts with evaluable data, no association between BRCA1 expression and outcomes was found. pERK expression was negatively associated with 3-mo PFS, but not 6-mo PFS. Cytoplasmic pERK expression was negatively associated with tumor response (p=0.03). No significant effect of BRCA-1 or pERK expression was found on OS. Conclusions: This trial showed B + C is an active regimen, especially in heavily pretreated mTNBC pts. Correlative data demonstrated a negative association between pERK expression and outcomes. A randomized phase II trial is in development. Clinical trial information: NCT01091454.

Ovarian cancer is a heterogeneous disease having the highest gynecologic fatality in the United States with a 5-year survival rate of 46.5%. Poor overall prognosis is mostly attributed to inadequate screening tools, and the majority of diagnoses occur at late stages of the disease. Due to genetic and biological underpinnings, ovarian high-grade serous carcinomas (HGSC) have etiologic evidence in the distal fallopian tube. Fallopian tube screening modalities are aggressively investigated, but few describe cytological characteristics of benign tubal specimens to help in the comparative detection of HGSC precursor cells. Here, we describe fimbrial cytomorphological and nuclear features of tubal specimens (n = 75) from patients clinically indicated for salpingectomy, bilateral or unilateral salpingo-oophorectomy, and hysterectomies for any diagnosis other than ovarian or peritoneal cancer. Fallopian tube histology was used as the diagnostic reference. A total of 75 samples had benign diagnoses. The benign cytological characteristics of fimbrial tubal specimens included ciliated cells in clustered arrangements with mild nuclear membrane irregularity, mild anisonucleosis, round and/or oval nuclei, hyperchromatic chromatin, and mild nuclear membrane irregularity. In contrast, none of the cytology samples had spindle-shaped nuclei, significantly marked anisonucleosis (n = 1), nor had hypochromasia as a characteristic feature. These cytological characteristics could be a potential area of distinction from HGSC precursor cells. Our study establishes cytomorphological characteristics of nonmalignant tubal cells which help underscore the importance of distinguishing malignant HGSC precursors through fimbrial brush sampling in minimally invasive approach.

Background: Exogenous lipoid pneumonia (ELP) is a rare benign entity without specific clinical or imaging presentation. Although cytological studies – either bronchoalveolar lavage (BAL) or fine-needle aspiration (FNA) – may be pursued in patients with ELP, a definitive diagnosis is frequently rendered only on histology. The aim of this study is to highlight the cytological features of ELP. Methods: A search of cytopathology (CP) and surgical pathology (SP) diagnoses of ELP was conducted. The corresponding clinical and imaging features were obtained, and the morphology, particularly the presence and size of the intracytoplasmic vacuoles and background, was assessed. Results: Nine cases of ELP were identified, including eight with corresponding CP and SP. A neoplasm was suspected in three based on imaging, but ELP was not in the differential clinically or radiographically in any. Among the cases, six patients had BALs and three FNAs. All of the samples showed multiple large vacuoles within macrophages with at least some equal to or larger than the size of the cell nucleus. Similar vacuoles were noted extracellularly on smears. Conclusions: ELP is typically described in case reports in the clinical or radiological literature. To the best of our knowledge, this represents the largest series of adult ELP in CP. When large vacuoles are present in macrophages in cytology specimens, at least a suspicion of ELP can be suggested to initiate appropriate therapy, identify/remove the inciting agent, and preclude a more invasive procedure.

Background: The 2014 Bethesda System recommends reporting the finding of benign-appearing, exfoliated endometrial cells on Papanicolaou (Pap) tests in women aged 45 years and older. We aimed to determine the significance of normal endometrial cells on liquid-based Pap tests in women aged 40 years and older and to correlate this finding with clinical factors and cytologic/histologic follow-up. Materials and Methods: We retrospectively identified all women aged 40 years and older who had benign endometrial cells (BECs) on Pap tests at our institution during a 6-year period. Histologic follow-up and outcomes were evaluated. Results: Among 18,850 Pap tests during the study period, 255 (1.4%) had findings of BECs and 159 (62.4%) of these women had follow-up Pap tests or subsequent tissue sampling by surgical procedures. Of the 159 cases, only 4 (2.5%) had significant endometrial pathologic processes, all endometrial endometrioid adenocarcinoma (three women had postmenopausal bleeding and 1 was perimenopausal with menorrhagia). No women between ages 40 and 45 years had significant pathologic findings and only one woman between 46 and 50 years (47 years) had an endometrial endometrioid carcinoma (1.5%). Women older than 47 years have higher odds (5.38) of having a significant endometrial lesion (P = 0.029) than those who are ≤47. Conclusion: Clinically significant endometrial lesions occurred predominantly in women older than 50 years (4.6%) and in only one woman between ages 46 and 50 years (1.5%). Therefore, endometrial sampling should be performed in women aged 47 years and older with BECs, especially when additional clinical indicators (e.g., postmenopausal bleeding) are recognized.

18 Background: Benign breast disease (BBD) is diagnosed in 1-2 million women/year in the US, and while these patients are known to be at substantially increased risk for subsequent development of breast cancer, existing models for risk assessment perform poorly at the individual level. Here, we describe a DNA-microarray-based transcriptional model for breast cancer risk prediction for patients with sclerosing adenosis (SA), a lesion found in ¼ of all BBD patients that is characterized by epithelial proliferation, disordered acinar architecture, and stromal fibrosis. Methods: A training set was developed from 86 patients diagnosed with sclerosing adenosis (SA), of which 27 subsequently developed cancer within 10 years (cases) and 59 remained cancer-free at 10 years (controls). A diagonal linear discriminate analysis (DLDA)-prediction model for prediction of cancer within 10 years (SA TTC10) was generated from transcriptional profiles of formalin fixed, paraffin-embedded (FFPE) biopsy-derived RNA. This model was tested on a separate validation case-control set composed of 65 SA patients. Results: The SA TTC10 gene signature model, composed of 35 gene features, achieved a clear and significant separation between case and control with receiver operating characteristic area under the curve of 0.913 in the training set and 0.836 in the validation set. Conclusions: Our results provide the first demonstration that benign breast tissue contains transcriptional alterations that indicate risk of breast cancer development, and that essential precursor biomarkers of malignancy are present many years prior to cancer development. Furthermore, the SA TTC10 gene signature model, which can be assessed on FFPE biopsies, constitutes a novel prognostic biomarker for patients with SA.

We describe a primary hepatic neuroendocrine tumor of a 57-year-old Thai woman who presented in 2004 with a suspicious mass in the left hepatic lobe. She underwent left hepatectomy for the 10.5-cm mass, calledintermediate grade neuroendocrine carcinoma of unknown origin,likely metastatic. The tumor recurred in 2007, then calledrecurrent primary hepatic neuroendocrine tumor(PHNET), and the patient underwent liver transplant. Because of similarity between the neuroendocrine tumor and a thyroid tumor—specifically, follicular-like characteristics—immunohistochemical stains for thyroglobulin, TTF1, and calcitonin were performed. However, all were negative. All imaging studies revealed no evidence of a primary lesion other than the liver mass. In 2008, the patient’s liver transplant failed because of ischemic cholangiopathy, and she underwent a second liver transplant. Seven years later, in 2015, she presented with metastatic neuroendocrine tumor of intermediate grade to the lung, consistent with metastatic PHNET. She underwent left upper-lobe wedge resection to remove the tumor. The patient is alive with no evidence of disease at 13 years after initial diagnosis. This rare variant of PHNET had thyroid-like morphologic characteristics but there is no evidence of primary thyroid tumor or thyroid markers in the primary and recurrent hepatic tumors and lung metastasis.