PD-1 and PD-L1 Expression in Male Breast Cancer in Comparison with Female Breast Cancer.

BACKGROUND: Male breast cancer is rare, as it represents less than 1% of all breast cancer cases. In addition, male breast cancer appears to have a different biology than female breast cancer. Programmed death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), seem to have prognostic and predictive values in a variety of cancers, including female breast cancer. However, the role of PD-1 and PD-L1 expression in male breast cancer has not yet been studied. OBJECTIVES: To compare PD-1 and PD-L1 expression in male breast cancer to female breast cancer and to evaluate prognostic values in both groups. PATIENTS AND METHODS: Tissue microarrays from formalin-fixed paraffin-embedded resection material of 247 female and 164 male breast cancer patients were stained for PD-1 and PD-L1 by immunohistochemistry. RESULTS: PD-1 expression on tumor-infiltrating lymphocytes was significantly less frequent in male than in female cancers (48.9 vs. 65.3%, p = 0.002). In contrast, PD-L1 expression on tumor and immune cells did not differ between the two groups. In male breast cancer, PD-1 and tumor PD-L1 were associated with grade 3 tumors. In female breast cancer, PD-1 and PD-L1 were associated with comparably worse clinicopathological variables. In a survival analysis, no prognostic value was observed for PD-1 and PD-L1 in either male and female breast cancer. In a subgroup analysis, female patients with grade 3/tumor PD-L1-negative or ER-negative/immune PD-L1-negative tumors had worse overall survival. CONCLUSIONS: PD-1 seems to be less often expressed in male breast cancer compared to female breast cancer. Although PD-1 and PD-L1 are not definite indicators for good or bad responses, male breast cancer patients may therefore respond differently to checkpoint immunotherapy with PD-1 inhibitors than female patients.

Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer.

Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.

Secretory breast carcinoma: a clinicopathological and immunophenotypic study of 15 cases with a review of the literature.

Secretory breast carcinoma is a rare breast cancer with indolent clinical behavior. Recent research showed that secretory breast carcinoma belongs to the phenotypic spectrum of basal-like breast carcinomas. In this study, a clinicopathological and immunophenotypic analysis of secretory breast carcinomas from 15 Chinese patients was conducted. This patient group consisted of 2 males and 13 females, with ages ranging from 10 to 67 years old (median, 36 years old). All patients presented with a painless and firm mass. Tumor size ranged from 10 to 55 mm. Most tumors were located in the outer upper quadrant of the breast. Two patients (2 of 13, 15%) displayed positive axillary lymph nodes. At the microscopic level, the presence of intracellular and extracellular secretory material was the most remarkable feature. Most cases showed mild dysplasia cytologically. All cases were negative for estrogen receptor, progesterone receptor and HER2. The expression rate of the basal-like marker (CK5/6 or epidermal growth factor receptor) was 87% (13 of 15). The basal-like phenotype was identified in 13 cases (87%). Follow-up time ranged from 10 to 55 months (median, 19 months). None of the cases had evidence of recurrence and metastasis. Our study reveals that secretory breast carcinoma is a distinct subset of invasive breast carcinoma, with expression of basal-like markers. It should be noted that secretory breast carcinoma is different from conventional basal-like breast carcinomas. Future studies are required to further understand the prognostic significance of the basal-like markers expression in secretory breast carcinomas.

Imatinib mesylate (Gleevec) in advanced breast cancer-expressing C-Kit or PDGFR-beta: clinical activity and biological correlations.

BACKGROUND: Novel molecular therapies for metastatic breast cancer (MBC) are necessary to improve the dismal prognosis of this condition. Imatinib mesylate (Gleevec) inhibits several protein tyrosine kinases, including platelet-derived growth factor receptor (PDGFR) and c-kit, which are preferentially expressed in tumor cells. We tested the activity of imatinib mesylate in MBC with overexpression of PDGFR or c-kit. Additionally, we sought to determine the biological correlates and immunomodulatory effects. PATIENTS AND METHODS: Thirteen patients were treated with Imatinib administered orally at 400 mg p.o. b.i.d. (800 mg/day), until disease progression. All patients demonstrated PDGFR-beta overexpression and none showed c-kit expression. RESULTS: No objective responses were observed among the 13 patients treated in an intention-to-treat analysis. All patients experienced disease progression, with a median time to progression of 1.2 months. Twelve patients have died, and the median overall survival was 7.7 months. No patient had a serious adverse event. Imatinib therapy had no effect on the plasma levels of the angiogenesis-related cytokines, vascular endothelial growth factor, PDGF, b-fibroblast growth factor, and E-selectin. Immune studies showed imatinib inhibits interferon-gamma production by TCR-activated CD4(+) T cells. CONCLUSION: Imatinib as a single agent has no clinical activity in PDGFR-overexpressing MBC and has potential immunosuppressive effects.

Non-Hodgkin's lymphoma presenting as a breast mass in patients with HIV infection: a report of three cases.

Breast involvement with non-Hodgkin's lymphoma (NHL) is rare. Patients with AIDS have an increased incidence of NHL, often with high-grade histology, extranodal presentation and aggressive clinical course. Lymphoma of the breast in patients with HIV-1 infection has not been reported. We reviewed our tumor registry database of all AIDS-associated NHL and report on the clinical presentation and long-term outcome of 3 patients with AIDS who presented with lymphomatous involvement of the breast.

Oral fluconazole for empiric treatment of prolonged Fever in neutropenic patients: prospective study in 250 consecutive patients after stem cell transplantation.

Neutropenic patients who continue to be febrile despite adequate broad-spectrum antibacterial treatment require empirical antifungal therapy. The aim of the present study was to evaluate the safety and efficacy of oral fluconazole for empirical antifungal therapy in neutropenic patients with persistent fever. A prospective cohort design was used. The study sample included 250 consecutive patients with high-risk stage II, III, or responding metastatic breast cancer who received high-dose chemotherapy (HDC) with autologous peripheral blood progenitor stem cell transplantation. Those with neutropenic fever lasting more than 72 hours despite broad-spectrum antibacterial coverage were treated with fluconazole. Treatment was continued until fever dropped and/or neutrophil count recovered with blood cultures remaining negative. Antifungal treatment was required in 173 patients (69%). There were no cases of documented deep systemic fungal infection. Two patients (<1%) had positive blood cultures for fungi. None of the patients experienced toxicity related to fluconazole. There was one transplant-related death. Thirty-one patients (18%) were unable to complete the oral fluconazole protocol because of severe mucositis, and they received intravenous fluconazole at the same dose, with similar efficacy. Oral fluconazole is a safe and effective alternative to amphotericin B for empirical early antifungal treatment in persistent neutropenic fever in breast cancer patients undergoing HDC with autologous stem cell support. Further study of oral fluconazole and amphotericin B as empirical agents in other groups of patients with persistent neutropenic fever is warranted.

Detection and purification of a novel 72 kDa glycoprotein male breast tumor associated antigen.

A male breast tumor associated antigen (MBTAA) was purified and partially characterized from human male breast tumor. Three protein peaks were obtained by DEAE-cellulose column chromatography of a crude extract of human male breast tumor tissues. Circulating antibodies against one of these peaks, MF1, which contained MBTAA, were observed in male breast cancer patients but not in normal male or male patients with carcinoma of other organs (stomach, colon, lung). The MBTAA was partially purified from MF1 by subjecting the fraction to SDS-PAGE and eluting the protein from band 3 (MB-3) and by subjecting MF1 to size exclusion-high performance liquid chromatography (SE-HPLC). The MBTAA was characterized as a glycoprotein with MW of approximately 72 kDa. It showed no immunological relatedness with TAG-72, a tumor associated antigen expressed in breast epithelial cells. A 72 kDa protein, immunologically related to MBTAA, was detected and partially purified from female breast tumor. The female breast cancer patients did not have circulating antibodies against this 72 kDa protein or MBTAA. Presence of 72 kDa glycoprotein MBTAA in MF1 and specificity of the anti-MBTAA antibodies in the sera of male breast cancer patients were further confirmed by Western blot analysis. Absence of anti-MBTAA antibodies in healthy men and in patients with other cancers suggested that expression of MBTAA may be malignancy-associated and is highly overexpressed in male breast cancer.

[Therapeutic effect of multimodal therapy, such as cryosurgery, locoregional immunotherapy and systemic chemotherapy against far advanced breast cancer].

A total of 6 breast cancer patients, 5 with local recurrent tumors on their anterior chest wall and 1 with far advanced primary breast tumor, underwent multimodal therapy in which cryosurgery was performed in combination with local injection of the non-specific immunopotentiator OK-432. This multimodal therapy was repeated as many times as possible. In addition, 3 patients whose general condition was relatively good were treated with mild chemotherapy. In every patient who underwent cryosurgery combined with locoregional immunotherapy, eradication or reduction of tumor was observed for several months. Of 3 patients who underwent cryosurgery, locoregional immunotherapy and systemic chemotherapy, the tumor burden decreased markedly in 2 patients and rapid tumor growth was suppressed in 1 patient, even though the diameter of tumor was over 5 cm in all cases. There were no side effects caused by either cryosurgery or locoregional immunotherapy. Little toxicity was observed throughout the mild chemotherapy. These results indicated that cryosurgery in combination with local injection of OK-432 should be a feasible modality against unresectable breast cancer on the chest wall, and that this therapeutic effect might be augmented by mild chemotherapy.

[Pigmented Paget's disease of the male nipple]. / Maladie de Paget pigmentée du mamelon chez l'homme.

BACKGROUND: Mammary Paget's disease unfrequently occurs in males, and may be pigmented in rare instances. Differential diagnosis with malignant melanoma relies on immunohistochemical studies. CASE REPORT: A case of Paget's disease of the nipple in a 76 year-old male is reported, clinically mimicking a malignant melanoma because of massive pigmentation. Histologically, large Paget's clear cells were intermingled with numerous melanin-rich dendritic melanocytes. An underlying ductal carcinoma was found. After differential immunohistochemical staining, diagnosis of Paget's disease could be unequivocally substantiated since Paget's cells stained for epithelial markers, c-erbB-2 and hormonal receptors, whereas protein S100 and HMB45 were negative. DISCUSSION: Pigmentation in mammary Paget's disease occurs preferentially in males. Pigmentation results from numerous melanocytes with abundant melanin in close contact with Paget's cells. An increased number of melanocytes may also be observed in cutaneous metastatic breast carcinomas. It could result from a chemotactic factor produced by neoplastic cells.

Comparison of immunoperoxidase staining of 3 different types of CD5 antibodies in a spectrum of breast lesions.

CONTEXT: We recently described a patient with chronic lymphocytic leukemia who presented with a breast carcinoma that stained positive for CD5 using a commercially available antibody (CD5-4C7, Novocastra, Newcastle upon Tyne, UK). OBJECTIVES: To study the distribution of CD5 immunoreactivity in tissue sections of a variety of benign and malignant breast lesions using the antibody CD5-4C7 and to compare the results with those obtained with 2 other commercially available CD5 antibodies (CD5/54/F6, Dako, Ely, Cambridgeshire, UK, and CD5/54/B4, Novocastra). DESIGN: Paraffin sections of 102 breast biopsy specimens with various diagnoses were examined using the avidin-biotin immunoperoxidase complex technique. SETTING: The histopathology department of a tertiary referral teaching hospital. RESULTS: The staining results obtained with CD5-4C7 were different from those obtained with the other 2 antibodies. With 4C7, the normal and benign biopsy specimens showed varying numbers of positive epithelial cells and lymphocytes. Heterogeneous positive staining was also present in 47 (78%) of 60 invasive female breast carcinomas and in all 3 male breast carcinomas examined. A statistically significant correlation was found between CD5 positivity and tumor grade, with grade 3 tumors being less likely to be CD5 positive than grades 1 and 2 (P =.0035). No correlation was found between CD5 positivity and patient's age, tumor histologic type, axillary lymph node status, or progesterone receptors. On the other hand, the CD5/54/F6 and CD5/54/B4 antibodies only stained lymphocytes and occasional normal breast ducts, mostly those showing apocrine metaplasia. All other normal benign and malignant epithelial cells were negative. CONCLUSIONS: Positive staining for CD5 using the antibody 4C7 is seen in normal and benign breast tissue and 78% of invasive breast carcinomas. The positivity is more common in low-grade tumors. No significant staining was seen with the 2 other CD5 clones used in this study. The significance of the positive staining obtained with CD5-4C7 is not obvious, but this clone may be more sensitive than the others, or it may be recognizing an epitope shared by another antigen.

Granular cell tumor of the male breast: report of a case.

We treated a 35-year-old male with a granular cell tumor in the right breast. Physical examination revealed a solid, flattened, round 3.2 x 2.5-cm mass with an irregular surface, covering skin fixation and right axillary lymphadenopathy. Mammography revealed a well-demarcated high-density mass with a minimal starburst appearance. Ultrasonography revealed a hypoechoic, nonhomogeneous mass with an acoustic shadow. Several enlarged lymph nodes in the right axilla were removed at the time of breast tumor excision. Histologically, the tumor featured nests of round or polygonal cells with abundant eosinophilic cytoplasmic granules and small round nuclei, and the enlarged lymph nodes in the right axilla exhibited no metastasis. Immunohistochemically, there was positive staining for S-100 protein, neuron-specific enolase, and vimentin. The tumor also stained for macrophage CD-68, alpha1-antichymotrypsin, and myoglobin. These immunohistochemical findings suggested the tumor cells to be undifferentiated mesenchymal cells which demonstrated the properties of neurogenic cells and histiocytes.

Plasmacytoma of the breast. A report of two cases diagnosed by aspiration biopsy.

BACKGROUND: Extramedullary plasmacytoma of the breast is an uncommon neoplasm, occurring either as a solitary tumor or as evidence of disseminated multiple myeloma. CASE: Two cases of plasmacytoma of the breast were diagnosed by fine needle aspiration cytology. Aspiration smears showed a dispersed population of plasmacytoid cells with eccentric nuclei, abundant cytoplasm and the characteristic paranuclear hof. CONCLUSION: The clinical, cytologic and immunophenotypic features of plasmacytoma are characteristic, and the importance of distinguishing these neoplasms from primary mammary tumors is important to avoid unnecessary surgery.

Immunoreactivity of prostate-specific antigen in male breast carcinomas: two examples of a diagnostic pitfall in discriminating a primary breast cancer from metastatic prostate carcinoma.

Prostatic-specific antigen (PSA) is regarded as a specific marker secreted by normal and neoplastic acinar epithelial cells of the prostate gland; its detection by immunocytochemistry has been accepted as an indication of metastatic prostate cancer. This is ascribed to the commonly held belief that PSA is not found in extraprostatic tissues. However, this concept has recently been challenged, based on the observations that certain nonprostatic tissues and their neoplasms can also secrete PSA. Such a questionable belief could result in a diagnostic pitfall when using immunostaining for PSA on fine-needle aspiration (FNAC) cytology samples to differentiate metastatic prostate cancer from a primary carcinoma of an extraprostatic organ. In this communication, two cases of primary carcinomas of the male breast are reported in which PSA immunopositivity on FNAC led to the suggestion of a diagnosis of metastatic carcinoma of the prostate. Diagn. Cytopathol. 1999;21:167-169.

Intratumoral aromatase in human breast, endometrial, and ovarian malignancies.

In human estrogen-dependent neoplasms such as breast, endometrioid endometrial, and surface epithelial-stromal ovarian carcinomas, intratumoral aromatase is considered to play important roles in converting circulating androgens derived from adrenal cortex and/or ovary to estrogens, possibly in association with 17 beta-HSD type 1 and estrogen sulfatase. Analysis of intratumoral aromatase in these estrogen-dependent neoplasms is important not only in understanding the development and biological behavior of these tumors, but also in the clinical management of these patients, because suppression of intratumoral aromatase by newly developed aromatase inhibitors may provide new potentials in endocrine therapy of these patients.