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Neoadjuvant therapy (NAT) is becoming a common approach to treat breast cancers. The most important advantage of NAT is the opportunity to evaluate the tumor response to treatment within few months after starting the medication. Pathology is the gold standard to determine the post therapy changes and response. An accurate and reproducible pathology report requires a multidisciplinary approach, a standard and appropriate handling of the gross specimen and recognizing the microscopic changes associated with a post NAT specimen. This review focuses on the standard approach for a post NAT breast specimen, based on the available guidelines and other related articles.

Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptor-positive (ER + ) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER + breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxia-inducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER + /HER2 − metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with the ESR1 mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α–dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.

Lapatinib (L) plus trastuzumab (T), with endocrine therapy for estrogen receptor (ER)+ tumors, but without chemotherapy, yielded meaningful response in HER2+ breast cancer (BC) neoadjuvant trials. The irreversible/pan-HER inhibitor neratinib (N) has proven more potent than L. However, the efficacy of N+T in comparison to pertuzumab (P) + T or L + T (without chemotherapy) remains less studied. To address this, mice bearing HER2+ BT474-AZ (ER+) cell and BCM-3963 patient-derived BC xenografts were randomized to vehicle, N, T, P, N+T, or P+T, with simultaneous estrogen deprivation for BT474-AZ. Time to tumor regression/progression and incidence/time to complete response (CR) were determined. Changes in key HER pathway and proliferative markers were assessed by immunohistochemistry and western blot of short-term-treated tumors. In the BT474-AZ model, while all N, P, T, N + T, and P + T treated tumors regressed, N + T-treated tumors regressed faster than P, T, and P + T. Further, N + T was superior to N and T alone in accelerating CR. In the BCM-3963 model, which was refractory to T, P, and P + T, while N and N + T yielded 100% CR, N + T accelerated the CR compared to N. Ki67, phosphorylated (p) AKT, pS6, and pERK levels were largely inhibited by N and N + T, but not by T, P, or P + T. Phosphorylated HER receptor levels were also markedly inhibited by N and N + T, but not by P + T or L + T. Our findings establish the efficacy of combining N with T and support clinical testing to investigate the efficacy of N + T with or without chemotherapy in the neoadjuvant setting for HER2+ BC.

Background: Human papilloma virus (HPV) is the most common sexually transmitted disease worldwide. α-genus HPV have oncogenic potential in anogenital skin and mucosa. Transplant patients have an increased incidence of β-genus HPV-associated cutaneous squamous cell carcinoma (cSCC). The host immune system is particularly important in the pathogenicity of HPV infection. The antibody-mediated, humoral immune response clears virus particles from body fluids and prevents re-infection. Cell-mediated immunity clears the virus from infected cells, generating immune memory. Impaired cell-mediated immunity is considered a primary risk factor in HPV-induced cSCC in the immunosuppressed population. Patients with chronic lymphocytic leukemia (CLL), a B-cell malignancy characterized by impaired humoral immunity, are at increased risk of developing cSCC. The purpose of this study is to explore the potential role of HPV in malignancies with impaired humoral response. Methods Primary cSCC tissue DNA was isolated from patients diagnosed with CLL. The tissue was analyzed for the presence of HPV. Diagnostic specimens underwent consensus dermatopathology review. Peripheral blood analytes and clinical parameters for disease course were statistically analyzed in conjunction with histopathology. Results Eleven patients with CLL contributed 37 cSCCs. In 49% of the lesions, HPV was detected. Among the cSCC lesions, 27% of the lesions contained β-genus HPV and 30% contained α-genus HPV. The most frequently reported virus was HPV-27 (α-genus), with 16% of lesions containing this variant which is frequently associated with cutaneous warts rather than cSCC. A majority of the HPV-containing lesions displayed moderate dermal lymphocytic inflammation. The lesions were often documented in sun exposed areas such as the scalp and face. Interestingly, HPV-16 and HPV-18, often found in anogenital epithelia, were detected in sun exposed skin in 14% of the lesions examined. In those patients who had documented immunoglobulins, all had hypogammaglobulinemia. Conclusions We examined clinical, histopathologic, and viral genotypes of the cSCCs in patients with CLL. It is widely accepted that CLL patients have a higher incidence and recurrence of cSCC; however, the characteristics of the lesions and the potential association to HPV has not been reported. In our cohort, the lesions were as likely to contain HPV from the α- or β- genus. HPV-27, normally associated with warts, displayed an atypical pathology. The presence of HPV-16 and -18 in sun exposed areas, suggests a novel pathology in compromised humoral immunity. Although our analysis derived some interesting associations, the role for HPV in cSCC in patients with impaired humoral immunity requires further characterization. This is particularly important as we explore the role of vaccinations in reducing HPV-associated malignancies. Citation Format: Preeya Bhavsar, Mugahed Hamza, Sepideh Mehravaran, Qin He, Steven Tyring, Peter Rady, Bhuvaneswari Krishnan, Gustavo Rivero, Daniel N. Cohen, Iberia Romina Sosa. The contribution of human papilloma virus infection to cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4898.

Glioma remains the most challenging solid organ tumor to treat successfully. Based on the capacity of stem cells to migrate extensively and target invading glioma cells, the transplantation of stem cells as a cell-based delivery system may provide additional tools for the treatment of gliomas. In addition to the use of modified stem cells for the delivery of therapeutic agents, unmodified stem cells have been shown to have growth-suppressing effects on tumors in vitro and in vivo. This review outlines the probable factors involved in tumor tropism and tumor growth suppression, with a specific focus on the use of unmodified stem cells in the treatment of gliomas. Based on these and further future data, clinical trials may be justified.

This prospective study aimed to compare the value of fine needle aspiration (FNA) cytology (FNAC) and flow cytometric immunophenotyping (FCI) with histopatopathology (HP) in the diagnosis and classification of non-Hodgkin lymphoma (NHL). Twenty-nine excised lymph nodes suspected of NHL were evaluated using FNAC, FCI, and HP. Specimens were divided into two equal parts; one for HP and the other for FNAC and FCI. Results were compared in terms of diagnosis (malignant, benign or reactive, and metastatic) and NHL class. With combined FNAC/FCI, 11 (37.9%) cases were diagnosed as NHL, 11 cases (37.9%) as reactive lymph node, six cases (20.6%) as Hodgkin's lymphoma, and one case (3.4%) as metastasis. HP revealed nine cases (31%) of NHL, five cases (17.2%) of reactive lymph nodes and all the diagnosed metastatic and Hodgkin's lymphoma. Considering histology as a gold standard method in diagnosis, the sensitivity, specificity, PPV and NPV of FNAC/FCI in differentiate malignant and benign lesion were 73.9%, 83.3%, 94.4%, and 45.5%, respectively and in differentiate NHL from others were 75%, 93.8%, 90%, and 83.3%, respectively. Cytology and HP in addition to FCI and HP are significantly different from determination of NHL lesions point of view (P = 0.001 and P < 0.0001, respectively). However, FCI can be considered as an adjunctive method for Cytology especially because Cytology is not competent enough to differentiate between benign lesions and Lymphoma. Additionally, FCI is shown to be an accurate method in classifying NHL. Diagn. Cytopathol. 2010. © 2010 Wiley-Liss, Inc.