Roger E. Moe

Effect of delay in radiation in the combined modality treatment of breast cancer

PURPOSE To study how the timing of radiation influences local control, overall survival, and disease-free survival in patients being treated with chemotherapy and radiation for a local-regional carcinoma of the breast. METHODS AND MATERIALS Over a ten year period, 105 patients received chemotherapy and radiation treatments for a local-regional breast cancer. The population was divided into two groups based on the timing of their radiation treatments. Forty-eight patients began their radiation within 6 months of their diagnosis (early radiation group). Fifty-seven patients had a delay in their radiation for 6 or greater months in order to first maximize chemotherapy treatments (delayed radiation group). There were no significant differences between the two groups with respect to nodal status, stage of the primary, estrogen receptor status, patient age, or type of surgery performed. The only prognostic parameter that was imbalanced was that of a greater percentage of patients with close or positive margins in the early radiation group compared to the delayed radiation group (69% versus 38%, p < 0.02). RESULTS Comparisons of local control, overall survival, and disease-free survival between the early radiation patients and delayed radiation patients all favored the early radiation group. Respective 8-year actuarial rates were: local control--98% vs. 76%, p = 0.004; overall survival--80% vs. 52%, p = 0.016; disease-free survival--71% vs. 48%, p = 0.008. The differences continued to be significant in a multivariate Cox regression model comparison: p = 0.011, p = 0.050, p = 0.009. There was only one death from intercurrent disease, so that overall survival approximated cause-specific survival to an accurate degree. CONCLUSIONS In patients requiring chemotherapy and radiation treatments for a local-regional breast cancer, a delay in the initiation of radiation for a period of 6 months or greater from diagnosis resulted in a higher local failure rate. Furthermore, this higher local failure rate was associated with an increased rate of distant metastases and a decreased overall survival rate.

Axillary web syndrome after axillary dissection

BACKGROUND Some patients undergoing axillary lymph node dissection (ALND) experience postoperative pain and limited range of motion associated with a palpable web of tissue extending from the axilla into the ipsilateral arm. The purpose of this study is to characterize the previously undescribed axillary web syndrome (AWS). METHODS To identify patients with AWS, a retrospective review was performed of all invasive breast cancer patients treated by a single surgeon (REM) between 1980 and 1996. Records were also reviewed of 4 more recent patients who developed AWS after undergoing sentinel node lymph node dissection (SLND) without ALND. RESULTS Among 750 sequentially treated patients, 44 (6%) developed AWS between 1 and 8 weeks after their axillary procedure. The palpable subcutaneous cords extended from the axillary crease down the ipsilateral arm, across the antecubital space, and in severe cases down to the base of the thumb. The web was associated with pain and limited shoulder abduction (< or = 90 degrees in 74% of patients). AWS resolved in all cases within 2 to 3 months. AWS also occurred after SLND. Tissue sampling of webs in 4 patients showed occlusion in lymphatic and venous channels. CONCLUSIONS AWS is a self-limiting cause of morbidity in the early postoperative period. More limited axillary surgery, with less lymphovenous disruption, might reduce the severity and incidence of this syndrome, although SLND does not eliminate its occurrence.

Internal mammary lymph node drainage patterns in patients with breast cancer documented by breast lymphoscintigraphy.

AbstractBackground: Metastases to internal mammary lymph nodes (IMN) may occur in patients with breast cancer and may alter treatment recommendations. The purpose of this study was to identify the frequency of IMN drainage in patients undergoing breast lymphoscintigraphy and sentinel lymph node dissection (SLND). Methods: The combined technique of peritumoral injection of radiocolloid and Lymphazurin blue for SLND was performed on 220 patients. All patients underwent preoperative lymphoscintigraphy before SLND. Lesion location by quadrant included: 110 upper outer (UOQ), 49 lower outer (LOQ), 30 upper inner (UIQ), 24 lower inner (LIQ), and 7 central. Results: Drainage to any nodal basin was observed in 184 of 220 patients (84%). IMN drainage was documented in 37 of 220 (17%) of patients. IMN drainage without evidence of axillary drainage occurred in 2 of 220 patients(1%). Drainage to the IMN based on quadrant location of the lesion was as follows: UOQ, 10%; LOQ, 27%; UIQ, 17%; LIQ, 25%; and central, 29%. Conclusions: Internal mammary lymph node drainage shown by breast lymphoscintigraphy is common. Tumors in all quadrants may drain to IMNs, although drainage is significantly more common from quadrants other than the UOQ. Further studies are needed to determine whether lymphoscintigraphy drainage patterns identify patients at the highest risk for IMN metastases who may benefit from radiotherapy.

Changing incidence of lobular carcinoma in situ of the breast.

Estimating the incidence of lobular carcinoma in situ (LCIS) of the breast is challenging because it lacks both clinical and mammographic signs and is usually an incidental finding in breast biopsies performed for other reasons. In general, population-based studies are believed to provide the most accurate measures, but few documenting changes in LCIS incidence rates over time have been reported. Age-adjusted age-specific LCIS incidence rates among women with no prior history of in situ or invasive breast carcinoma from 1978 to 1998 were obtained from nine population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) Program. Linear trends were evaluated using negative binomial regression. Overall, LCIS incidence rates increased fourfold (95% confidence interval, 2.9–5.6) over the study period. Specifically, they rose from 0.90/100,000 person-years in 1978–80 to 2.83/100,000 person-years in 1987–89, but then increased only modestly up to 1996–98 where the incidence rate was 3.19/100,000 person-years. However, among women 50–79 years of age, LCIS incidence rates increased continuously over the studys duration. In 1996–98, 50–59 year-olds had the highest incidence rate (11.47/100,000 person-years) and experienced the greatest absolute increase in incidence over the study period (9.48/100,000 person-years). LCIS incidence rates have steadily increased from 1978 to 1998 only among postmenopausal women. Further research is required to assess what factors are contributing to these trends.

C-erbB-2 oncogene protein in in situ and invasive lobular breast neoplasia.

Lobular carcinoma in situ (LCIS) has uncertain malignant potential; biologic markers that will identify patients at risk for a poor clinical outcome have been sought actively. Amplification of the c‐erbB‐2 protooncogene has been correlated with poor prognosis in invasive mammary carcinoma, and immunohistochemical evaluation for expression of the oncogene protein has been correlated with gene amplification. The authors retrospectively evaluated 62 cases of lobular neoplasia for expression of the c‐erbB‐2 gene product on formalin‐fixed, deparaffinized sections, using two monoclonal anti‐erbB‐2 (p185) antibodies (c‐neu Ab3 and m‐erb) and one polyclonal anti‐erbB‐2 antibody (pAb 1) by the avidin‐biotin‐peroxidase method. All 62 cases were negative with the pAb 1 antibody; one of 62 cases was weakly positive with the c‐neu Ab3 in a membranous pattern. Expression of c‐erbB‐2 gene product was identified on adjacent invasive ductal carcinoma in one case and in adjacent ductal carcinoma in situ in another. None of 15 cases if infiltrating lobular carcinoma was positive with either of the two anti‐c‐erbB‐2 antibodies. Strong positivity was found on benign epithelium in one case, demonstrating epitheliosis. In summary, evidence of expression of the c‐erbB‐2 gene product was found in one of 57 cases of LCIS and none of 15 cases of invasive lobular carcinoma. This suggests that, in contrast to reported data concerning intraductal and invasive ductal carcinoma, c‐erbB‐2 oncogene amplification and/or overexpression does not play a significant role in the progression of lobular breast neoplasia.

Risk of contralateral breast cancer among women with carcinoma in situ of the breast

BACKGROUND Information is limited on the risk of contralateral breast cancer after a diagnosis of breast carcinoma in situ (BCIS). METHODS In western Washington, between 1974 and 1993, 1929 women with a first primary ductal carcinoma in situ (DCIS) and 282 women with a first primary lobular carcinoma in situ (LCIS) were followed for contralateral breast cancer. Rates of contralateral invasive breast cancer and BCIS were compared with population rates of first primary breast cancer using Poisson regression to adjust for age and calendar year. RESULTS The rate of contralateral invasive disease after BCIS was approximately twice the population rate for women with DCIS and three times the population rate for women with LCIS; relative rates decreased somewhat with increasing time since diagnosis of LCIS, but were fairly stable after DCIS. The relative rate of contralateral DCIS after BCIS was substantially higher than for contralateral invasive disease, but dropped dramatically after the first year after the initial BCIS, especially among women with LCIS. Contralateral BCIS usually was of the same histologic type as the initial BCIS; histologic concordance of BCIS was 71% for women with an initial LCIS and 78% for women with DCIS. CONCLUSIONS Data suggest that the rate of contralateral invasive breast cancer is elevated for at least 5 years after a diagnosis of BCIS compared with the rate of first primary breast cancer in the population, and that the rate is only slightly higher for women with LCIS than for women with DCIS. The markedly elevated rate of contralateral DCIS may result in large part from increased medical surveillance of women diagnosed with BCIS, especially during the first year after the initial diagnosis.

Identification of Multiple Proliferative Growth Factors in Breast Cyst Fluid

Gross cystic disease is a common benign breast disease that is associated with a twofold to fourfold increase in breast cancer risk. Both diseases are hormonally induced and may share a common biochemical environment conducive to abnormal proliferative responses. A large collection of breast cyst fluid samples was analyzed for growth factors associated with cell proliferation: epidermal growth factor (EGF), insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), platelet-derived growth factor (PDGF), transforming growth factor-alpha (TGF-alpha), and transforming growth factor-beta (TGF-beta). The data demonstrate that significant amounts of proliferative growth factors are present in breast cyst fluid of all cyst subtypes. The presence of IGF-II, PDGF, and TGF-beta in breast cyst fluid was confirmed for the first time. EGF, PDGF, and TGF-beta concentrations in breast cyst fluid were several times greater than reported for serum; IGF-I and IGF-II concentrations were several times lower. In the first 100 samples tested, no TGF-alpha was detected. Only EGF and IGF-II levels demonstrated a consistent correlation with apocrine type 1 cysts. These results demonstrated that effective concentrations of proliferative growth factors are in breast cyst fluid and suggest that adjacent breast tissue may be a probable source of synthesis. Growth factor profiles of breast cyst fluid may indicate the presence in breast tissue of a hormonal and proliferative environment permissive to subsequent cancer growth.

Demonstration of the functional anatomy of the canine gastric antrum

Abstract Technics are described for visual delineation of the corpus-antrum boundary in canine stomachs. These technics involve various dye-stuffs, neutral red, toluidine blue, Congo red, and fluorescein. This study shows that differences in intravenous dye excretion in the gastric corpus as compared with the gastric antrum can be exploited to reveal anatomic limits of the antrum, Color differences obtained in this way were observed to correspond to areas of different pH values, but the color differences result basically from the presence or absence of dye excretion which is a major feature of this study. Gastric color boundaries from dyestuffs were marked and compared with histologic corpusantrum boundaries. Color boundaries obtained are accurate and reproducible. Furthermore, color boundaries are easily seen; use of a layer of gauze upon gastric mucosa provides a white background against which dyestuffs are vivid. Some comparative features of these dyestuffs are discussed. Possible applicability of these technics includes operations in which the gastric corpus and antrum are to be separated or in which the corpus-antrum boundary is to be marked for future reference in experiments.

Retinoids, Retinoic Acid Receptors, and Breast Cancer

Retinoids comprise both naturally and synthetically occurring compounds that have been proven to be differentiation agents for a variety of neoplasias, including breast cancer and promyelocytic leukemia in animal models and humans. They offer a unique panoply of therapeutics for the prevention or treatment of breast cancer. Nonetheless, considerable controversy remains as to the efficacy and potential toxic side-effects and as to which group of patients may most benefit. In this article, we review evidence of retinoid efficacy in breast cancer in humans and in animal models and provide possible mechanisms of retinoid action in breast cancer treatment, focusing on the roles of the different retinoic acid receptors and the metabolic pathways necessary for gene activation and cellular homeostasis.

Identification of a unique biological tumor marker in human breast cyst fluid and breast cancer tissue

Breast cyst fluid from 35 women was stratified into risk groups based on personal and family history of breast cancer. Mitogenic activity in breast cyst fluid of women at highest risk to develop breast cancer was significantly higher than the activity in the lowest-risk group. There was a direct dose-dependent relationship between mitogenic activity and increased risk of developing breast cancer. Size-exclusion chromatography showed that breast cyst fluid from women at highest risk contained two peaks of growth factor activity: less than 6 kilodaltons (kd), identified as human EGF (epidermal growth factor), and 6 to 18 kd. Moderate-risk group samples demonstrated only the single less than 6 kd peak, whereas the lowest-risk group had insignificant growth-promoting activity. Breast cancer tissue analyzed in a similar manner revealed a predominant 6- to 14-kd peak of mitogenic activity demonstrating the same acid- and heat-stability found in breast cyst fluid.