Antigens and antibodies cross-reactive to the murine mammary tumor virus in human breast cyst fluids.

Human breast cyst fluids were shown to contain low concentrations of IgA (15-78 micrograms/ml) and IgG (33-145 micrograms/ml). The IgA:IgG ratios in individual breast cyst fluids ranged from 1:0.6 to 1:4. These levels are considerably higher than their ratio in serum (1:7). IgA from 33% of the 40 fluids examined, and IgG from 10% of the fluids, reacted with the murine mammary tumor virus (MuMTV). The reactivity was detected by an enzyme-linked immunosorbent assay that measures antibody binding to both the envelope glycoprotein and core protein of the virus. In a second series of experiments. IgA from 28% of 40 breast cyst fluids reacted only with MuMTV while IgA from 30% of the fluids was reactive with both MuMTV and the Rauscher murine leukemia virus. Antigen reactive with antiserum to the 28,000-dalton MuMTV core protein (p28), was also identified in a 165,000-g pellet fraction from breast cyst fluids. In individual fluids, the extent of IgA binding to MuMTV was positively correlated (P less than or equal to 0.01) with the binding of anti-p28 antibody to the pellet of the breast cyst fluid. Fractions with the buoyant density of retroviruses (1.16-1.18 g/ml) or their cores (1.21-1.25 g/ml) were isolated from breast cyst fluids. These fractions contained a DNA polymerase capable of utilizing the reverse transcriptase-specific template, dG12-18 x poly rCm. In addition, they reacted with antiserum to MuMTV p 28 but not with antiserum to the 30,000-dalton Rauscher murine leukemia virus core protein.

Prognosis in T2N0M0 stage I breast carcinoma: a 20-year follow-up study.

In a study of prognosis in node-negative breast carcinoma, we investigated 293 T2N0M0 patients treated by mastectomy and axillary dissection with a median follow-up of 19.8 years. The probability of surviving 20 years considering all causes of death was 41.3% +/- 3.0%. Recurrence-free survival (Kaplan-Meier estimate) was 68.6% +/- 3% at 10 years and 63.2% +/- 3.1% at 20 years. The estimated probability of cure determined by the method of Brinkley and Haybittle was 63% (95% confidence interval [Cl], 55% to 72%). Prognosis was related to primary tumor size with the best separation (P = .06) when tumors from 2.1 to 3.0 cm (33% chance of recurrence at 20 years) and from 3.1 to 5.0 cm (44% chance of recurrence at 20 years) were compared. The histologic tumor type was prognostically important. Recurrence at 20 years was not significantly different for patients with invasive duct (34%) and lobular (42%) carcinoma. Women with special types (medullary, mucinous, papillary, etc) of carcinoma had a 25% chance of recurrence. Subsequent contralateral breast carcinoma was diagnosed in 29 patients, and four of these were fatal, accounting for only 4.6% of breast carcinoma deaths. Thirty-two patients (10.9%) developed a nonmammary malignant neoplasm (NMMN) after the ipsilateral breast carcinoma, and 69% of these lesions were fatal. Although the chances of recurrence at 20 years related to tumor size and type did not differ statistically in the series, there were trends that suggest that T2N0M0 patients can be stratified into recurrence risk groups based on tumor size and histologic type. These factors should be taken into consideration in the design and analysis of clinical adjuvant therapy trials. Measures for the early detection of common NMMNs should be included in the routine follow-up of T2N0M0 breast carcinoma patients.

Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up.

PURPOSE: This study was undertaken to define prognostically favorable and unfavorable subgroups of node-negative breast carcinoma patients by employing conventional pathologic data. PATIENTS AND METHODS: Seven hundred sixty-seven women with T1N0M0/T2N0M0 breast carcinoma treated consecutively from 1964 through 1970 by modified or radical mastectomy without systemic adjuvant therapy were analyzed at a median follow-up duration of 18 years. RESULTS: Size and histologic type of the carcinoma were crucial discriminants of prognosis. We defined a prognostically favorable group of 219 patients (29%) with infiltrating duct or lobular carcinoma < or = 1.0 cm in diameter or special tumor types < or = 3.0 cm. This group had a relapse-free survival rate of 91% at 10 years and 87% at 20 years. The less favorable group (548 patients, 71%) with infiltrating duct or lobular carcinoma greater than 1.0 cm and special tumor types greater than 3.0 cm had relapse-free survival rates of 73% and 68% at 10 and 20 years, respectively. The frequency of nonmammary malignant neoplasms (NMMN) was similar to that of contralateral carcinoma. Deaths due to NMMN were seven times more frequent than deaths due to contralateral carcinoma. CONCLUSION: Nearly 30% of these node-negative patients, identified on the basis of tumor size and type, had an extremely favorable prognosis. There is insufficient evidence to warrant the routine use of adjuvant therapy in this group unless new forms of treatment prove to be less toxic and/or more effective in enhancing relapse-free survival. Early detection of NMMN should be an important part of the follow-up of node-negative breast carcinoma patients.

Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 18 years.

Prognostic factors have been examined in 644 patients with tumor-node-metastasis (TNM) stage T1 breast carcinoma treated by mastectomy and followed for a median of 18.2 years. Overall, 148 patients (23%) died of recurrent breast carcinoma. Eighteen (3%) were alive with recurrent disease and 478 (74%) were alive or died of other causes without recurrence. Unfavorable clinicopathologic features were larger tumor size (1.1 to 2.0 cm v less than or equal to 1 cm), perimenopausal menstrual status, the number of axillary lymph node metastases, poorly differentiated grade, presence of lymphatic tumor emboli (LI) in breast tissue near the primary tumor, blood vessel invasion (BVI), and an intense lymphoplasmacytic reaction around the tumor. Median survival after recurrence for the entire series was 2 years. This was not significantly influenced by tumor size, the number of axillary nodal metastases, the type of treatment for recurrence, or the interval to recurrence. The proportions surviving 5 and 10 years after recurrence were 17% and 5%, respectively. Among T1N0M0 cases, the chance of a local recurrence was 2.8% within 20 years. Median survival of T1N0M0 cases after local recurrence (4.5 years) was significantly longer than after systemic recurrence (1.5 years). A similar trend (3.7 v 2.0 years), not statistically significant, was seen in T1N1M0 patients, who had a 6.5% chance of local recurrence within 20 years. Median survival following systemic recurrence detected 10 or more years after diagnosis in T1N0M0 and in T1N1M0 patients was significantly longer than the median survival for systemic recurrences found in the first decade of follow-up. This difference did not apply following local recurrence in either T1N0M0 or T1N1M0 cases. It is evident that patients with T1 breast carcinoma can be subdivided into differing prognostic groups and this must be taken into account when considering the role of adjuvant chemotherapy for stage I disease. Systemic adjuvant treatment may prove to be beneficial for patients with unfavorable prognostic factors, while women with an especially low risk for recurrence (eg, T1N0M0 tumor 1.0 cm or less) might be spared such treatment.

A long-term follow-up study of survival in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma.

This study was undertaken to investigate the long-term survival and the probability of "cure" in a group of 644 patients treated by mastectomy for T1 breast carcinoma. After a median follow-up of 18.2 years, 23% were dead of recurrent breast carcinoma, 3% were alive with recurrent disease, and 74% had not experienced a recurrence. The probability of recurrence was directly related to the initial extent of the disease. Overall, 16% of recurrences and 25% of deaths due to disease occurred in the second decade of follow-up. The proportion of recurrences detected in the second decade was inversely related to the stage of the primary tumor at diagnosis. When stratified by tumor size, T1N0M0 patients with tumors 1.0 cm or less in diameter had a significantly better 20-year recurrence-free survival (86%) than did T1N0M0 patients with tumors 1.1 to 2.0 cm (69%). When observed and expected survival curves were compared by the method of Brinkley and Haybittle, it appeared that 80% of T1N0M0 patients with tumors 1 cm or less might be cured at 20 years, whereas for those in the 1.1- to 2-cm group, the proportion cured was indeterminate, but might be as high as 70%. A potentially cured group could not be identified among T1N1M0 patients, but an estimated 52% of these patients did not have a recurrence within the nearly 20-year follow-up period. These data are important when one considers the proper role of adjuvant therapy for stage I disease. Patients with tumors larger than 1 cm and those with axillary lymph node metastases may have an improved recurrence-free survival as a result of systemic adjuvant treatment, while women in the T1N0M0 group with an especially favorable recurrence-free survival, particularly those with tumors 1 cm in diameter or smaller, might be spared adjuvant therapy.

Menstrual timing of treatment for breast cancer.

Although the hormone dependency of breast cancer has been recognized for nearly a century, the influence on disease progression of cyclical hormonal levels among premenopausal women has not been extensively researched. The findings of recent studies, assessing the effect on prognosis of the hormonal milieu at the time of surgery, have been conflicting. However, several reports have noted improved survival among patients with positive, axillary lymph nodes surgically treated in the later phase of the menstrual cycle when progesterone levels are elevated. Biologic support for the influence of menstrual timing is provided by cyclical patterns of cell division and cell death observed in normal breast tissue as well as potential tumor cell dissemination during surgery among patients with positive axillary nodes. Immune parameters, which also respond to cycling endogenous hormones, may influence the metastatic potential of circulating tumor cells. Comparisons among studies of menstrual timing of surgery have been complicated by differences in cycle divisions, extent of primary surgery, frequency of adjuvant therapy, duration of follow-up, and analytic procedures. Although several clinicians are now scheduling breast surgery of premenopausal women in relation to day of the menstrual cycle, a majority of surgeons have deferred consideration of menstrual timing until additional research is available. While waiting 5-10 years for the results of prospective studies, additional retrospective analyses, using carefully collected data, may provide clinical guidance. With increasing concern for issues related to women's health, multidisciplinary studies will be required to adequately characterize the influence of the menstrual cycle and other aspects of women's reproductive physiology on breast cancer and other medical conditions.

Survival and prognostic factors in node-negative breast cancer: results of long-term follow-up studies.

Seven hundred sixty-seven patients treated at the Memorial Sloan-Kettering Cancer Center from 1964 through 1970 by mastectomy and axillary dissection have now been followed for a median of 18 years. This unusual database consists of a consecutive series of women cared for by physicians specialized in the treatment of breast cancer in one institution. The data suggest that patients with T1, N0, M0 tumors of 1 cm or less may be "cured" by mastectomy and axillary dissection, the estimated proportion of "cured" patients being 89%. The data also suggest that node-negative patients can be placed in categories of risk for recurrence on the basis of primary tumor size.

Iridium-192 implants for primary breast cancer: experience with placement at the time of wide local excision.

An Ir-192 boost is a technique frequently used to deliver an additional dose of radiation therapy to the tumor bed following breast conserving surgery and combined with external beam radiation therapy to the entire breast for patients with early breast cancer. Traditionally these catheters are placed following completion of 4500-5000 cGy, as a separate procedure. This paper described a Pilot Study identifying placement of the catheters at the time of primary wide local excision, or re-excision in 52 patients. The key to the success of this technique is the achievement of complete hemostasis in the primary cavity, the presence of the radiation oncologist during the surgical procedure itself, and closure of the wound prior to placement of the catheters. Details of the technique, and preliminary patient results are presented.

Breast carcinoma presenting with axillary lymph node metastases. An analysis of specific histopathologic features.

Forty-three patients with metastatic carcinoma in axillary lymph nodes from an unknown primary site were studied. Thirty-one women (72%) were subsequently identified as having primary carcinoma in the ipsilateral breast. Based on the histologic patterns of the metastasis, patients were divided into three groups. Type I axillary lymph node metastases were composed of sheets of large, apocrine-like pleomorphic cells with pale to granular pink cytoplasm, large nuclei, and prominent nucleoli. This type was found in two-thirds of the cases. Type II metastases were readily recognizable as characteristic of breast carcinoma and included glandular, cribriform, and papillary patterns and comedonecrosis. Type III metastases demonstrated a mixture of the two previous patterns. Patients proven to have breast carcinoma ranged in age from 33 to 83 (average 58). Among the 31 cases with proven breast carcinoma, mammography was abnormal in 11 (35%). In the 12 other cases (18%), no primary in the breast or other site was demonstrated. Patients not proven to have breast carcinoma had a similar age distribution, comparable proportions of histologic patterns of metastases, and similar survival results to those with a demonstrated breast carcinoma, and none of the 12 patients were later shown to have another primary. The findings described here indicate that when mammary carcinoma presents initially with axillary metastases, it often has a distinctive histological pattern. In most cases this consists of relatively large, apocrine-like cells growing diffusely without forming glands or papillary structures. A minority of metastases have patterns (comedonecrosis; trabecular, glandular, or trabecular growth) more characteristic of the usual spectrum of breast carcinoma. Awareness of this morphological diversity should assist the pathologist in suggesting the breast as a primary site when the initial manifestation is an axillary lymph node metastasis.

Occult axillary lymph node metastases from breast cancers with intramammary lymphatic tumor emboli.

Serial sections were performed on the axillary lymph nodes from 28 women with mammary carcinoma and intramammary lymphatic tumor emboli. Occult metastases were demonstrated in nine women (32%), all less than 2 mm in diameter. During the 10 years of follow-up, no difference in recurrences was found between this group (33%) and those without occult metastases (37%). Serial sectioning of lymph nodes in this group of patients does not appear to be helpful in prognosis.

Monoclonal antibodies detect occult breast carcinoma metastases in the bone marrow of patients with early stage disease.

Thirty-five to 40% of patients with operable breast carcinoma develop metastases after primary therapy. There is a need for more specific prognostic parameters to identify patients who are most likely to benefit from adjuvant therapy. The success of such treatment stems from its ability to eradicate preclinical microscopic metastases. The bone marrow is an accessible and frequent site of breast carcinoma metastases. Following studies of Redding et al. (16), we used monoclonal antibodies that recognize membrane and cytoskeletal antigens expressed by epithelial cells (C26, T16, AE-1) in an immunohistochemical assay to find cancer cells in bone marrow aspirates. The assay can detect one cancer cell among 50,000-100,000 hematopoietic cells. None of the 44 control bone marrows (from normal individuals and patients with leukemias and lymphomas) contained antigen-positive (extrinsic) cells. We found extrinsic cells in the bone marrow of 35% (18 of 51) of patients with operable breast carcinoma; no extrinsic cells were identified by routine bone marrow cytology in these patients. Twenty-seven percent (six of 22) of patients with negative lymph nodes had antigen-positive cells, while 41% (12 of 29) of patients with lymph node metastases had such cells. Similarly, 23% (three of 13) of patients with TNM stage I disease, 38% (13 of 34) of patients with stage II disease, and 50% (two of four) of patients with stage III disease had extrinsic cells. In those cases where extrinsic cells were identified, stage II patients with negative lymph nodes and patients with stage I disease were found to have fewer such cells in their marrow than patients with lymph node metastases and patients with stage II disease. These trends did not reach the level of statistical significance in this small number of patients. The presence of extrinsic cells did not correlate with tumor size of lymphatic invasion around the tumor. We conclude that the epithelial cells detected in the bone marrow of the patients with breast carcinoma were carcinoma cells based on the following criteria: (a) they expressed both membrane and cytoplasmic epithelia-specific antigens, (b) they possessed the cytologic characteristics of malignant epithelial cells, and (c) these cells were not detected in the bone marrow from normal individuals or patients with nonepithelial neoplasms involving the bone marrow. We have shown that the technique described here can detect occult metastases in bone marrow and that the presence of extrinsic cells correlates with some established predictors of prognosis. Long-term clinical correlative follow-up studies are now underway.

Angiosarcoma and other vascular tumors of the breast.

Vascular tumors of the breast, with the exception of perilobular hemangiomas, are generally considered to be malignant. The pathologic and clinical features of 40 patients with angiosarcoma of the breast and 12 with other vascular tumors of the breast were reviewed. Three general histologic patterns of growth were identified among the angiosarcomas and were found to correlate closely with prognosis. Whereas 10 of the 13 patients in histologic Group I were alive and free of disease with an average follow-up of nearly 6 years, only two of 16 Group III patients were free of disease, and 14 have died. The six Group II patients had a survival similar to those in Group I. In this series the disease-free survival at 3 years was 41% and at 5 years 33%, much better than that reported in previous reviews of mammary angiosarcoma. The data also indicated that adjuvant chemotherapy, specifically actinomycin D, is effective in some and possibly all patients with angiosarcoma of the breast. The 12 other vascular lesions had distinctly different morphologic features, a benign clinical course, and should probably not be viewed as angiosarcomas. However, total excision of all vascular lesions of the breast is essential in order to determine both the diagnosis and the appropriate therapy.

Role of contralateral breast biopsy in infiltrating lobular cancer.

BACKGROUND: Although infiltrating lobular carcinoma (ILC) is known to be associated with higher rates of bilaterality, contralateral breast biopsies are not routinely performed in such patients. METHODS: The pathology reports of all patients with ILC admitted to Memorial Sloan-Kettering Cancer Center between 1970 and 1980 were retrospectively reviewed. The incidence of contralateral biopsies, random and directed, was determined. The findings on contralateral biopsy were evaluated with respect to age of the patient, nodal status of the ipsilateral cancer, and multicentricity of the primary lesion. RESULTS: Of the 275 patients undergoing mastectomy for ILC, 130 (47%) had contralateral biopsies. Twenty-two were directed biopsies and 108 were random biopsies. On random biopsy 11 (10%) patients were found to have infiltrating carcinomas and seven (6%) were found to have intraductal cancer. Multicentric invasive disease in the ipsilateral breast was found to be predictive of a positive contralateral biopsy (p = 0.01). CONCLUSIONS: Despite the current trend toward less extensive surgery for breast cancer, random contralateral breast biopsy is indicated in patients with ILC.

Multicentricity and bilaterality in invasive breast carcinoma.

Multicentricity and bilaterality are well-established characteristics of breast carcinoma, but little is known about the relationship of these variables with each other. This question was explored by analyzing the data pertaining to 880 women with invasive breast carcinoma. Patients with multicentric carcinoma had bilateral disease more often than those whose carcinoma was apparently limited to a single quadrant. Among women who had lobular carcinoma in situ coexisting with infiltrating duct carcinoma or infiltrating lobular carcinoma, bilaterality and multicentricity were significantly more common than they were among patients whose only lesion was infiltrating duct or medullary cancer. Other variables associated with bilaterality and multicentricity were degree of ductal differentiation, tumor size, nodal status, type of tumor margin, intensity of lymphoid infiltrate, and menstrual status. Age at diagnosis and estrogen receptors were related to bilaterality but not to multicentricity. The following variables proved to be unrelated to bilaterality and multicentricity: family history of breast carcinoma, height, weight, and parity. The data obtained in this study tend to support a conclusion that multicentricity and bilaterality are manifestations of similar factors involved in the neoplastic transformation of mammary gland epithelium leading to the development of breast cancer.

Contralateral breast carcinoma: an assessment of risk and prognosis in stage I (T1N0M0) and stage II (T1N1M0) patients with 20-year follow-up.

Among 644 patients with a small (T1) primary breast carcinoma who were followed up for a median of 18.2 years, subsequent contralateral breast carcinomas were detected in 57 of 610 women (9%) who had a contralateral breast at risk. The average annual hazard rate for contralateral carcinomas was 8/1000 patients at risk per year without significant fluctuations throughout the 20 years of follow-up. Recurrences were caused by 9 of 57 (16%) subsequent contralateral carcinomas, and 4 of the 57 patients (7%) died of recurrent contralateral carcinomas. Contralateral carcinomas were responsible for 5.1% (9 of 176) of all recurrences of breast carcinomas and 2.6% (4 of 153) of breast carcinoma deaths. Surveillance of the contralateral breast must continue throughout a patient's lifetime. Detection and treatment of subsequent lesions at an early stage is a beneficial result of follow-up, especially in women whose first carcinoma is likely to have been cured.

Cutaneous melanoma of the breast.

A study of 115 cutaneous melanomas of the breast demonstrated that these neoplasms follow different metastatic patterns than do primary carcinomas of the breast and require a different therapuetic approach. Lesions located below a 3 cm from the clavicle metastasized exclusively to the axillary nodes regardless of location. None of 19 internal mammary node chains examined histologically contained tumor deposits. Microstaging of the primary lesion correlated closely with prognosis and lymph node metastasis. Treatment by mastectomy (radical, modified, extended radical) offered no advantage over local excision of the primary plus axillary dissection. The latter procedure is recommended for all cutaneous melanomas of the breast which require node dissection. Mastectomy is not indicated unless the breast is in the field of wide local excision. Internal mammary node dissections are not indicated.

Needle-localized mammographic lesions. Results and evolving treatment strategy.

From January 1981 to December 1987, 932 needle-localization breast biopsies were performed at our institution for mammographically detected abnormalities. We reviewed 531 needle-localization breast biopsy procedures performed during two periods (January 1981 to June 1984, n = 311; and January to August 1987, n = 220) to compare results and treatment patterns, and to determine the prevalence of the missed lesions. Mammographic abnormalities detected on routine screening accounted for a larger proportion of needle-localization breast biopsies in the later series (94 [30%] of 311 vs 94 [43%] of 220). However, the rate at which carcinoma was identified remained constant at 29% as did the percentage of cancers that were invasive (46% vs 51%). Overall, the rate of malignant diagnoses after needle-localization breast biopsy was lowest in asymptomatic women undergoing routine screening mammography (44 [24%] of 188) and significantly higher in women undergoing mammographic follow-up of the contralateral breast after treatment for breast cancer (28 [43%] of 65). There were seven missed lesions in 531 needle-localization breast biopsies, necessitating a second procedure in six and interval mammograms in one.

Estrogen receptor protein of breast cancer in patients with positive nodes. High recurrence rates in the postmenopausal estrogen receptor-negative group.

In 448 patients with positive axillary lymph nodes who were treated with mastectomy at Memorial Sloan-Kettering Cancer Center, New York, from 1973 to 1978, estrogen receptor (ER) status was associated with survival. With a median follow-up of 75 months, significant differences were noted in the 288 postmenopausal patients; ER-positive patients had better six-year disease-free survival than ER-negative patients (60% vs 45%), as well as better overall survival. These differences were true in subgroups with one to three and four or more involved nodes. The addition of adjuvant systemic therapy had no significant effect on either ER-positive or ER-negative patients. The need for new imaginative systemic programs in the subgroup of ER-negative postmenopausal patients with breast cancer with positive nodes is apparent.

Axillary lymphadenectomy. A prospective, randomized trial of 13 factors influencing drainage, including early or delayed arm mobilization.

Greater amount and duration of postoperative wound drainage after lymphadenectomy impede healing. We evaluated the influence of early vs delayed initiation of shoulder mobilization on postoperative drainage. Fifty-seven women with clinical stage I or II breast cancer were randomized to either early (postoperative day 2) or delayed (postoperative day 5) shoulder motion. Early vs delayed time of exercise initiation had no effect on total amount or duration of drainage, either as an inpatient or outpatient. The two groups were determined to be homogeneous as to age, breast size, weight, height, obesity, previous biopsy, excision of pectoralis minor, excision of thoracodorsal complex, level of axillary dissection, total number of lymph nodes, number of positive lymph nodes, lymphatic vessel invasion (with negative lymph nodes), and whether the dominant hand was on the side operated on. The two factors predicting greater drainage were large numbers of positive lymph nodes and no previous surgical biopsy (as in one-step procedure).

Inflammatory breast cancer.

Historically, the prognosis of inflammatory breast cancer has been poor. We conducted a retrospective review to evaluate the recent Memorial Sloan-Kettering Cancer Center experience, to evaluate the role of combination chemotherapy, and to compare the effect of surgery and radiation on local/regional failure. Fifty-six patients with local/regional inflammatory breast cancer diagnosed between 1975 and 1984 were identified. All were treated with combination chemotherapy. Overall 5-year survival was 45% with a 5-year disease-free survival rate of 37%. Twenty-one patients were treated with induction chemotherapy followed by mastectomy and adjuvant chemotherapy. Survival and disease-free survival rates were similar to those achieved in patients treated with mastectomy followed by chemotherapy. Residual cancer was found in all 21 patients treated with induction chemotherapy, with extensive disease present in 18, including six of seven complete responders. The local/regional failure rate was 34%.