Prognostic significance of in situ carcinoma associated with invasive breast carcinoma. A natural experiment in cancer immunology?

BACKGROUND: Our previous studies indicate that the in situ phase of mammary carcinogenesis is characteristically associated with cell-mediated immunity (CMI against an immunogen shared by most breast carcinomas. Such reactivity is inversely correlated with stage and appears to impede in situ-to-invasive progression and lethality from invasive breast carcinoma. If in situ carcinomas are indeed associated with ambient, prognostically favorable immunity against such an immunogen, one would expect lethality from invasive breast carcinoma to be reduced in patients with a diagnosis of a prior, simultaneous, or subsequent in situ breast carcinoma. The present study provides a test of such relationships. METHODS: Patient survival was analyzed for 129,394 female patients with invasive breast carcinoma diagnosed in areas covered by the Surveillance, Epidemiology, and End Results (SEER) Program based at the National Cancer Institute (NCI). Patients were classified according to whether they had a prior, simultaneous, or subsequent in situ breast carcinoma and survival was examined for up to 15 years subsequent to diagnosis using life tables and the Cox regression model. RESULTS: The findings indicate that patients with an invasive breast carcinoma who had a prior, simultaneous, or subsequent in situ breast carcinoma did experience significantly better survival than comparison groups of patients who either did not have an associated cancer of any type, had an associated invasive breast carcinoma, or had an in situ or invasive cancer of non-breast origin. CONCLUSIONS: Our prior and current observations warrant more direct studies of the prognostic, therapeutic, and prophylactic significance of the in situ carcinoma-associated type of specific CMI in breast cancer patients.

Prognostic significance of cellular immunity to autologous breast carcinoma and glycoprotein 55.

Using a skin window (SW) procedure, we evaluated post-operative cell-mediated immunity (CMI) to autologous breast cancer with reference to its prognostic significance, the nature of the immunogen, and the therapeutic implications. It appears that SW reactivity to autologous breast cancer is prognostically favorable per se and is independent of the prognostic significance of the nuclear grade of the cancer cells; SW reactivity to autologous breast cancer reflects CMI to a determinant(s) that is expressed by glycoprotein 55, the principal envelope glycoprotein of the RIII-murine mammary tumor virus; the glycoprotein 55-like CMi determinant(s) is more regularly expressed by preinvasive than by invasive breast cancers; tumor antigenicity and host reactivity may vary independently; and postoperative monitoring of CMI to autologous breast cancer is prognostically and therapeutically important.

Skin window reactivity to autologous breast cancer. An index of prognostically significant cell-mediated immunity.

The relationship between cell-mediated immunity (CMI) to autologous breast cancer tissue and subsequent clinical behavior has been studied by one of the authors since 1953. In this article the prognostic significance of CMI as measured by a skin window (SW) procedure is reported. The procedure examines cellular responses to coverslip-mounted sections of autologous breast cancer tissue that have been applied to a microabrasion of the skin. Using criteria routinely employed in conventional hematologic and pathologic diagnoses, diverse patterns of SW responses can be identified. Specific patterns are recognizable that are consistent with CMI and that vary significantly with stage and subsequent behavior of the disease. Intrastage variations in behavior were found for patients with invasive breast cancer according to nuclear grade (NG) and postoperative SW reactivity to autologous breast cancer. Positive SW reactivity was associated with a significantly reduced risk of metastases and also appeared to impede the occurrence of metachronous second primary invasive breast cancers. The findings demonstrate the current value of NG and SW response characteristics with regard to prognosis and immunotherapy. Moreover, they are consistent with the development of immunoprophylaxis.

Canine mammary epithelial neoplasms: biologic implications of morphologic characteristics assessed in 232 dogs.

We studied 232 dogs that underwent mastectomy for mammary epithelial neoplasms. The mastectomy specimens were evaluated according to structural parameters found to be prognostically significant in human mammary neoplasms, such as grade of atypia in non-invasive proliferations of duct epithelium, extent of malignant disease, and nuclear differentiation in malignant neoplasms. In this study, the biologic behavior of mammary lesions was assessed according to the frequency of development of de novo or recurrent invasive carcinoma within two years. Our data indicate that we can recognize structural variables which permit classification of mammary neoplasms into categories with distinct patterns of biologic behavior. In addition to normotypic proliferative lesions and invasive malignant neoplasms, we were able to identify precancerous atypic and non-invasive malignant neoplasms that are considered precursor lesions in women. Also, as in women, nuclear differentiation was found to be a prognostically significant variable. Lymphoid cellular reactions, considered to be structural correlates of host-tumor immune responses in women, were noted in 35% of dogs with precancerous or malignant neoplasms. Application of the described parameters should facilitate comparative studies of canine and human mammary carcinogenesis and use of the dog as a model for the development of new therapeutic modalities and immunoprophylaxis of human mammary cancer.

Antitumor immunity in breast cancer patients. Biologic and therapeutic implications.

As judged by in vivo and in vitro indices of cellular immunity, mammary carcinogenesis appears to be associated with immunogenic changes in the transformed cells and prognostically favorable antitumor cell-mediated immunity in the host. The prognostically favorable cell-mediated immunity appears to be directed against a component(s) which is shared by most stage 0 in situ breast cancers and the major envelope glycoprotein (gp55) of RIII murine mammary tumor virus. Progressive disease is associated with a loss of gp55-like tumor immunogenicity and/or anti-gp55 cell-mediated immunity of the host. It is appropriate that measurements of tumor immunogenicity and tumor-specific cell-mediated immunity of the host be included in the prognostic assessment and therapeutic decisions regarding individual patients. Such data are particularly pernitent to the development and evaluation of immunotherapeutic and immunoprophylactic protocols.

Cellular hypersensitivity of gp55 of RIII-murine mammary tumor virus and gp55-like protein of human breast cancers.

Previous studies suggested that immunogenic breast cancer tissues contained a component(s) that is antigenically similar to some component of murine mammary tumor virus (MuMTV) and resembles the glycoprotein, M.W. 55,000 (gp55), of RIII-MuMTV in molecular weight and charge density. This investigation measured in vitro cellular hypersensitivity responses of breast cancer patients to RIII mouse milk, purified RIII-gp55, C3H-MuMTV, autologous and homologous breast cancer tissues, gp50 of A-MuMTV, and preparations of Rauscher leukemia virus and Mason-Pfizer monkey virus. Particular attention was paid to cross-reactivity between gp55 and the other targets. The data indicate that responsiveness to C3H-MuMTV and RIII milk are linearly correlated with responsiveness to gp55. A preferential relationship was demonstrable between responses to gp55 and to those breast cancer tissues containing a gp55-like protein component (S-p50). The critical role of a gp55-like protein as the antigen responded to by breast cancer patients' in leukocytes was also suggested by the ability of anti-gp55 antiserum to decrease leukocyte responsiveness to RIII-gp55, C3H-MuMTV, and breast cancer tissues. In vitro cellular hypersensitivity against RIII-gp55 was preferentially found in prognostically favorable cases with immunogenic lesions. Further studies are needed to test the possibility that gp55 might be of value in the immunodiagnosis of early breast cancer, the monitoring of prognostically significant cellular hypersensitivity, and the induction of such hypersensitivity (immunoprophylaxis).

Prognostically significant protein components of human breast cancer tissues.

Cryostat sections of clinicopathologically characterized breast cancer tissues were eluted with phosphate-buffered 0.9% sodium chloride solution, pH 7.2. The proteins were then characterized by polyacrylamide gel electrophoresis with and without prior treatment with sodium dodecyl sulfate. Approximately 65% of the brease cancer tissue eluates contained a prominent protein fraction with a molecular weight of 47,000 to 55,000 (p50). No such component was found in 15 of 17 eluates of benign breast tissue. Charge density studies disclosed that the p50 component included three populations of proteins that could be characterized according to the migration relative to gp55 derived from RIII murine mammary tumor virus, namely, fast (F-p50), intermediate (I-p50), and slow (S-p50). Prognostically favorable pathological characteristics, i.e., stage, nuclear grade, and lymphoreticuloendothelial responses, were proportionately most frequently found among S-p50 bbreast cancers and were least frequently found among F-p50 breast cancers. It appears that the S-p50 component acts in vivo as a prognostically significant immunogen. Further knowledge of the relationship between protein characteristics and clinicopathological features of human breast cancers would contribute to our understanding of mammary carcinogenesis and biological behavior.

Biological considerations of tumor-specific and virus-associated antigens of human breast cancers.

In vivo and in vitro studies bearing on tumor-specific and viral-associated antigenicity of human breast carcinomas were reviewed with particular attention to the following clinical considerations: (a) breast carcinomas arise in a nonrandom fashion; (b) in situ carcinomas precede invasive breast carcinomas; (c) invasive breast carcinomas behave in a heterogeneous fashion. Microscopically demonstrable lymphoreticuloendothelial responses, skin window tests, and leukocyte migration tests all indicate that tumor-specific antigenicity develops in assoication with the early phases of mammary carcinogenesis. Such antigenicity is maximally expressed in in situ carcinomas without associated invasive breast cancer and minimally in invasive breast cancers with metastases. Immunogenic breast cancer tissues commonly contain a protein component the antigenic and physicochemical properties of which are similar to those of a protein component of murine mammary tumor virus. Advances in our understanding and control of human mammary carcinogenesis and biological behavior are dependent on the clinicopathological characterization of individual patients and their breast tissues as well as on the analytical procedures used.

Prognostically favorable immunogens of human breast cancer tissue: antigenic similarity to murine mammary tumor virus.

A leukocyte migration procedure was utilized to test cellular hypersensitivity of breast cancer patients' leukocytes to autologous and homologous breast cancer tissues and to murine milk containing murine mammary tumor virus (MuMTV). The in vitro responsiveness of the leukocytes and the antigenicity of breast cancer tissues were compared with in vivo prognostically favorable lymphoreticuloendothelial (L-RE) responses seen microscopically at the time of mastectomy and with the results of skin window tests of cellular hypersensitivity. The data suggest that immunogens appear in the in situ phase of the disease and provoke prognostically favorable L-RE responses. These immunogens possess antigenic similarity to some component(s) of MuMTV. Progression of the disease is associated with or preceded by a loss of tissue immunogenicity and/or diminished specific cellular hypersensitivity. The findings are pertinent to investigations of human mammary carcinogenesis and immunoprophylaxis.