Paclitaxel plus carboplatin and durvalumab with or without oleclumab for women with previously untreated locally advanced or metastatic triple-negative breast cancer: the randomized SYNERGY phase I/II trial.

Chemo-immunotherapy is the first-line standard of care for patients with PD-L1 positive metastatic triple-negative breast cancer (mTNBC). SYNERGY (NCT03616886) is a dose-finding phase I and a randomized phase II, open-label trial evaluating if targeting the immunosuppressive adenosine pathway can enhance the antitumor activity of chemo-immunotherapy. The phase I part included 6 patients with untreated locally-advanced or mTNBC to determine the safety and recommended phase II dose of the anti-CD73 antibody oleclumab in combination with the anti-PD-L1 durvalumab and 12 cycles of weekly carboplatin and paclitaxel. In the phase II part, 127 women were randomized 1:1 to receive chemo-immunotherapy, with (arm A) or without (arm B) oleclumab. The primary endpoint was the clinical benefit rate at week 24, defined as stable disease, partial or complete response per RECIST v1.1. Secondary endpoints included objective response rate, duration of response, survival outcomes (progression-free survival and overall survival), and safety. The trial did not meet its primary endpoint, as the 24-week clinical benefit rate was not significantly improved by adding oleclumab (43% vs. 44%, p = 0.61). Exploratory median progression-free survival was 5.9 months in arm A as compared to 7.0 months in arm B (p = 0.90). The safety profile was manageable in both arms.

Borderline phyllodes tumour of the breast with eosinophilic inclusion bodies: Case report and molecular sequencing.

INTRODUCTION AND IMPORTANCE: The presence of eosinophilic inclusion bodies in the breast is very rare and fewer than 20 cases were described in the literature. Herein we report the first case of borderline phyllodes tumour associated with this kind of cells. To the best of our knowledge, this is also the first time that a molecular sequencing is made targeting the stroma cells with inclusion bodies. CASE PRESENTATION: A 33-yr-old woman presented a large mass in the right breast. Imaging techniques by mammogram and ultrasonographic examination were performed. After multidisciplinary approach, a breast conserving surgery has been decided. Microscopic analysis, immunohistochemical stains and molecular tests were performed on the lesion. The proposed diagnosis is borderline phyllodes tumour with eosinophilic inclusion bodies. CLINICAL DISCUSSION: Inclusion bodies are typically found in the infantile digital fibromatosis. Finding them in extradigital fibromatosis is rare. Their signification is still unclear. Some studies suggest a disturbance in the metabolism of proliferating myofibroblasts. CONCLUSION: The presence of inclusion bodies in breast tumour do not seem to have a prognosis impact. It might be interesting to perform others molecular tests on lesions with eosinophilic inclusion bodies to discover potential mutations.

Comparison Between Manual and Automated Assessment of Ki-67 in Breast Carcinoma: Test of a Simple Method in Daily Practice.

BACKGROUND: In the era of "precision medicine," the availability of high-quality tumor biomarker tests is critical and tumor proliferation evaluated by Ki-67 antibody is one of the most important prognostic factors in breast cancer. But the evaluation of Ki-67 index has been shown to suffer from some interobserver variability. The goal of the study is to develop an easy, automated, and reliable Ki-67 assessment approach for invasive breast carcinoma in routine practice. PATIENTS AND METHODS: A total of 151 biopsies of invasive breast carcinoma were analyzed. The Ki-67 index was evaluated by 2 pathologists with MIB-1 antibody as a global tumor index and also in a hotspot. These 2 areas were also analyzed by digital image analysis (DIA). RESULTS: For Ki-67 index assessment, in the global and hotspot tumor area, the concordances were very good between DIA and pathologists when DIA focused on the annotations made by pathologist (0.73 and 0.83, respectively). However, this was definitely not the case when DIA was not constrained within the pathologist's annotations and automatically established its global or hotspot area in the whole tissue sample (concordance correlation coefficients between 0.28 and 0.58). CONCLUSIONS: The DIA technique demonstrated a meaningful concordance with the indices evaluated by pathologists when the tumor area is previously identified by a pathologist. In contrast, basing Ki-67 assessment on automatic tissue detection was not satisfactory and provided bad concordance results. A representative tumoral zone must therefore be manually selected prior to the measurement made by the DIA.

Post-Neoadjuvant Treatment Strategies for Patients with Early Breast Cancer.

Pre-surgical treatments in patients with early breast cancer allows a direct estimation of treatment efficacy, by comparing the tumor and the treatment. Patients who achieve a pathological complete response at surgery have a better prognosis, with lower risk of disease recurrence and death. Hence, clinical research efforts have been focusing on high-risk patients with residual disease at surgery, who may be "salvaged" through additional treatments administered in the post-neoadjuvant setting. In the present review, we aim to illustrate the development and advantages of the post-neoadjuvant setting, and to discuss the available strategies for patients with early breast cancer, either approved or under investigation. This review was written after literature search on main scientific databases (e.g., PubMed) and conference proceedings from major oncology conferences up to 1 August 2022. T-DM1 and capecitabine are currently approved as post-neoadjuvant treatments for patients with HER2-positive and triple-negative breast cancer, respectively, with residual disease at surgery. More recently, other treatment strategies have been approved for patients with high-risk early breast cancer, including the immune checkpoint inhibitor pembrolizumab, the PARP inhibitor olaparib and the CDK 4/6 inhibitor abemaciclib. Novel agents and treatment combinations are currently under investigation as promising post-neoadjuvant treatment strategies.

First Case Report of a Uterine Angiolipoleiomyoma With KRAS and KIT Mutations.

Angiolipoleiomyoma is a very rare lesion of the uterus. To the best of our knowledge, only 20 cases have been described in the literature. It is an insufficiently defined entity, which is not included in the WHO classification. This lesion may be therefore underdiagnosed and underestimated. We describe here a case of a 58-yr-old woman who underwent routine gynecological examination. Ultrasonography revealed a heterogeneous myometrial mass, while magnetic resonance imaging showed a voluminous corporeal and fundic myometrial mass protruding into the uterine cavity. A total hysterectomy was performed. The macroscopic examination revealed an intramural solitary round mass with a heterogeneous cut-surface. Microscopically, the lesion consisted of an admixture of smooth muscle, adipose tissue, and blood vessels. Desmin was positive, while HMB45 was negative in the tumor. Molecular tests were performed and revealed, for the first time to our knowledge, a case of an angiolipoleiomyoma harboring KRAS and KIT mutations.

Intraoperative Evaluation of Resection Margins in Breast-Conserving Surgery for In Situ and Invasive Breast Carcinoma.

BACKGROUND: The challenge of breast-conserving surgery (BCS) is to remove the entire tumour with free margins and avoid secondary excision that may adversely affect the cosmetic outcome. Consequently, intraoperative evaluation of surgical margins is critical. The aims of this study were multiple. First, to analyse our methodology of intraoperative examination of the resection margins and to evaluate radiological and pathological methods in the assessment of the surgical margins. Second, to evaluate the factors associated with positive margins in our patient population. M&M: The data on the resection margin status of 290 patients who underwent BCS for invasive carcinoma or ductal carcinoma in situ (DCIS) between 2009 and 2016 were reviewed. RESULTS: In the cohort of BCS with invasive carcinoma, the negative predictive value was 97.4% for intraoperative assessment by radiography and 81.8% for intraoperative assessment by pathology. The re-operation rate among cases without intraoperative assessment was 23.6% compared to 7.3% among cases with intraoperative assessment (P = .003). Margin status was significantly associated with tumour size, histological subtype (invasive lobular carcinoma), and multifocality. In the population of BCS with DCIS, margin status was significantly associated with preoperative localisation and intraoperative margin assessment (P = .03). CONCLUSION: There is no statistical difference between pathological and radiological intraoperative assessment. Tumour size, lobular subtype, and multifocality were found to be significantly associated with positive margins in cases with invasive carcinoma, whereas absence of intraoperative margin assessment was significantly associated with positive margins in cases with DCIS. Therefore, intraoperative margin assessment improves the likelihood of complete excision of the lesion.

Osseous Metaplasia in Low-grade Ovarian Serous Carcinoma With a BRAF Mutation: A Case Report.

A 44-yr-old woman presented with lower, painless abdominal discomfort and a vacuolated mass measuring 12 cm on the right-hand side of the pelvis. She subsequently underwent a bilateral salpingo-oophorectomy. An osseous lesion was identified in the left ovary, which was hard in consistency and was associated with a multicystic complex lesion. Microscopic examination of the left ovary showed clusters of serous cells with moderate atypia, surrounded by a desmoplastic stroma with large areas of bone matrix. To the best of our knowledge, this is the first reported case of low-grade serous carcinoma with osseous metaplasia and a BRAF mutation.

KRAS Mutation in Serous Borderline Tumor of the Testis: Report of a Case and Review of the Literature.

Ovarian-like epithelial tumors of the testis, including serous borderline tumors, are rare entities. We report the case of a 60-year-old man with a left intratesticular mass who had a radical orchidectomy. Histologically, the tumor was identical to the ovarian counterpart showing a well-delineated cystic lesion characterized by intraluminal papillae. The papillae are lined by atypical cuboidal or ciliated cells and are associated with psammoma bodies. The tumor cells express cytokeratin 7 (CK7), cytokeratin 5-6 (CK5-6), cancer antigen 125 (CA125), estrogen (ER), progesterone (PR), Wilm's tumor gene (WT1), paired box gene 8 (PAX8), Ber-EP4, and epithelial membrane antigen (EMA). The diagnosis of a serous borderline tumor of the testis was proposed. Mutation testing using next-generation sequencing showed a Q61K KRAS gene mutation. To the best of our knowledge, this is the second case report of a serous borderline tumor of the testis with a Q61K KRAS gene mutation.

Predictive factors of lymph node metastasis and effectiveness of intraoperative examination of sentinel lymph node in breast carcinoma: A retrospective Belgian study.

Recently, several trials demonstrated the safety of omitting axillary lymph node dissection in clinically N0 patients with positive sentinel nodes in select subgroups. However, this fact is still troublesome to clarify to surgeons and clinicians, as they used to perform intraoperative examination of the sentinel node and axillary dissection for many years. Hence, we decided to review our practice. This is to firstly highlight the predictive factors of node metastasis and secondly, to evaluate the effectiveness of intraoperative examination of the sentinel node. There were 406 total procedures. The rate of positive lymph nodes in the final diagnosis was 27%. Factors associated with metastasis were age, tumour size, TNM classification, tumour grade, vascular invasion, molecular classification and KI-67 index. The rate of reoperation was 6.2% in cases with final positive nodes, however, the complementary ALND was justified in only 2.7%. Forty-nine percent of SLN were examined during surgery (IOESLN), whereby the false negative rate was 11.8%. Sixty-three intraoperative examinations were necessary to prevent a second operation on a patient. We recommend changing the clinical management of the axilla, resulting in fewer ALNDs in selected cN0, SLN-positive patients. In keeping with recent large clinical trial (ACOSOG Z0011, AMAROS and OTOASOR) data, our results support that intraoperative exam in selected cN0, SLN-positive Belgian patients is no longer effective.

P53 and PIK3CA Mutations in KRAS/HER2 Negative Ovarian Intestinal-Type Mucinous Carcinoma Associated with Mature Teratoma.

Primary ovarian intestinal-type mucinous carcinomas associated with mature teratoma are rare and represent less than 3% of all primary ovarian neoplasms. The molecular profile of these tumors is still controversial. We report here the first case of mucinous ovarian tumor in which mutation of the PIK3CA and P53 genes could be demonstrated by the next generation sequencing technique without KRAS mutation or HER2 amplification. Our data suggest that these mucinous carcinoma variants probably present an extremely complex molecular biology profile that should be known in the future to stratify therapeutic outcomes and potential targeted therapies, particularly in recurrent disease.

Vulval Intestinal/Enteric Heterotopia in a Patient with Crohn's Disease.

Intestinal/enteric heterotopia of the vulva is an extremely rare disease with only 3 cases described in the literature. We report here an unusual case of this disease occurring in a 26-year-old patient in a context of Crohn's disease. To the best of our knowledge, such type of association has not been previously described. The potential origins of these lesions including metaplastic transformation, dysontogenetic changes, or epithelial colonic displacement/implantation are discussed.

Low grade malignant eccrine spiradenoma of the vulva: case report, review of the literature and discussion about the role of p53 and HPV.

BACKGROUND: Malignant eccrine spiradenoma is one of the rarest sweat-gland tumors. Here, we describe a rare case of low grade malignant eccrine spiradenoma located at the vulva. CASE PRESENTATION: The vulvar lesion was described as a mass measured 3.5 cm and located in the dermis and subcutis with no attachment to the epidermis. The neoplasm was arranged in ragged sheets or solid nodules sometimes with focal necrosis. The tumor cells had hyperchromatism, pleomorphism, and prominent nucleoli with high mitotic index and KI-67 estimated at 70-80%. CONCLUSIONS: It's only the fifth case of malignant eccrine spiradenoma localized at the vulva. This is the first time that an HPV genotyping was made in this type of lesion with no HPV found while the p16 expression was diffuse. Moreover, it's the first time that a p53 mutation is detected by sequencing in this location.

Invasive ductal carcinoma arising in borderline phyllode tumor: A potential role of PIK3CA mutation.

INTRODUCTION: Carcinomatous lesions associated with phyllodes tumors are extremely rare and are found in less than 1% of all cases. To date, the molecular biological mechanisms associated with this carcinomatous transformation remain unknown. PRESENTATION OF CASE: We present here the case of a 61-year-old patient with invasive ductal of no special type (NST) carcinoma originating in a borderline phyllode tumor with mutation in the PIK3CA gene. DISCUSSION: To the best of our knowledge, this mutation has never been described in this type of association. CONCLUSION: Based on these data, we can better understand the ethiopathogenic molecular mechanisms in this type of lesion. Consequently, they could also in the future give rise to new therapeutic alternatives.

Quantification of stromal reaction in breast carcinoma and its correlation with tumor grade and free progression survival.

Cancer progression results from a complex interplay between tumor cells and the extracellular milieu. In breast carcinoma, the stromal microenvironment has been suggested to play a major role in promoting tumor growth, progression, and invasion. The stroma of 154 resected specimens of invasive breast carcinoma of no special type was quantified using a digital image analyzer. Statistical analyses were performed between the quantity of stroma and survival, as well as between progression-free survival and clinicopathological data. Levels of myofibroblastic stroma varied from 0-46%, with a median of 15.1% and a standard deviation of 7.5. The myofibroblastic stromal reaction was statistically greater in grade 2 and 3 tumors (p = 0.029). Furthermore, there was a trend for worse progression-free survival in the group of node-negative tumors with strong smooth-muscle actin stromal expression (Log rank = 0.075). The present study demonstrates that the myofibroblastic reaction of breast invasive carcinoma of no special type is not merely a passive reaction, but seems to be an integral part of the neoplastic process by facilitating tumor progression and invasion. Additional, larger studies on mechanisms of stromal change are needed and may potentially lead to novel treatments.

Adenolipoleiomyoma Polyp of the Uterus: A Case Report and Review of the Literature.

Adenolipoleiomyoma is a very rare lesion of the uterus. Only four cases were reported. We describe one case of adenolipoleiomyoma presenting as a polyp in a postmenopausal woman with menorrhagia. Adenolipoleiomyoma is a very rare lesion and the histogenesis remains unclear. We discuss the origin and the differential diagnosis of this lesion.

PIK3CA and p53 Mutations by Next Generation Sequencing in Lymphoepithelioma-Like Carcinoma of the Endometrium.

Lymphoepithelioma-like carcinoma of the endometrium is a very rare variant of endometrial carcinoma characterized by syncytial nests of pleomorphic epithelial cells and heavy infiltration of the stroma by lymphocytes (in particular CD8 cytotoxic T-lymphocytes) and plasma cells. Until now, only five cases have been characterized in this location. This report describes the clinicopathological and the molecular features of this unusual tumor. In particular, using the next generation sequencing (NGS) technique, we have demonstrated that this tumor could be associated with PIK3CA and p53 gene mutations. These data have not been reported to date and suggest that lymphoepithelioma-like carcinoma of the endometrium shares common molecular features with high grade endometrioid and serous-like endometrial carcinoma which are associated with poor outcome. Nevertheless, in endometrial lymphoepithelioma-like carcinoma, the alterations on cell cycle, apoptosis, and/or senescence secondary to p53 mutations could potentially be counterbalanced by the antitumoral response induced by CD8 cytotoxic T-lymphocytes numerous in these tumors.

Expression of the glucocorticoid receptor in breast cancer-associated fibroblasts.

Cancer- associated fibroblasts (CAFs) are actively involved in breast carcinoma. Our previous study demonstrated that the majority of these CAFs were smooth muscle actin (SMA) positive and were therefore termed peritumoral myofibroblast (PMY). Glucocorticoid, linked or not with its receptor (GR), has been postulated to serve a major role in normal breast and breast carcinoma; however, their role in CAFs remains poorly understood. The aim of the present study was to assess the presence of GR in breast CAFs and particularly in PMY in 56 cases of invasive breast carcinoma in correlation with clinicopathological parameters, by immunohistochemistry. GR was observed in CAFs in 51 cases (91%) and were more frequent in luminal A subtype (19/19 cases; 100%). The stromal expression was statistically correlated with the tumor grade (P=0.03), the Ki-67 index (P=0.003) and the presence of GR in the epithelial component (P=0.01). The demonstration of a frequent expression of GR in breast CAFs may serve as an interesting target for future therapeutics for the regulation of the tumoral breast microenvironment.