Frontline Science: Myeloid-derived suppressor cells (MDSCs) facilitate maternal-fetal tolerance in mice.

During successful pregnancy, a woman is immunologically tolerant of her genetically and antigenically disparate fetus, a state known as maternal-fetal tolerance. How this state is maintained has puzzled investigators for more than half a century. Diverse, immune and nonimmune mechanisms have been proposed; however, these mechanisms appear to be unrelated and to act independently. A population of immune suppressive cells called myeloid-derived suppressor cells (MDSCs) accumulates in pregnant mice and women. Given the profound immune suppressive function of MDSCs, it has been suggested that this cell population may facilitate successful pregnancy by contributing to maternal-fetal tolerance. We now report that myeloid cells with the characteristics of MDSCs not only accumulate in the circulation and uterus of female mice following mating but also suppress T cell activation and function in pregnant mice. Depletion of cells with the phenotype and function of MDSCs from gestation d 0.5 through d 7.5 resulted in implantation failure, increased T cell activation, and increased T cell infiltration into the uterus, whereas induction of MDSCs restored successful pregnancy and reduced T cell activation. MDSC-mediated suppression during pregnancy was accompanied by the down-regulation of L-selectin on naïve T cells and a reduced ability of naïve T cells to enter lymph nodes and become activated. Because MDSCs regulate many of the immune and nonimmune mechanisms previously attributed to maternal-fetal tolerance, MDSCs may be a unifying mechanism promoting maternal-fetal tolerance, and their induction may facilitate successful pregnancy in women who spontaneously abort or miscarry because of dysfunctional maternal-fetal tolerance.

Genetic variants in platelet factor 4 modulate inflammatory and platelet activation biomarkers.

BACKGROUND: African Americans suffer from higher prevalence and severity of atherosclerosis compared with whites, highlighting racial and ethnic disparities in cardiovascular disease. Previous studies have pointed to the role of vascular inflammation and platelet activation in the formation of atherosclerotic lesions. METHODS AND RESULTS: We explored the role of genetic variation in 4 chemokine/chemokine receptor genes (CX3CR1, CX3CL1, CXCR3, and PF4) on systemic inflammation and platelet activation serum biomarkers (fractalkine, platelet P-selectin, platelet factor 4 [PF4], and tumor necrosis factor-α). In total, 110 single nucleotide polymorphisms were tested among 1042 African Americans and 763 whites. The strongest association with serum PF4 levels was observed for rs168449, which was significant in both racial groups (P value: African Americans=0.0017, whites=0.014, combined=1.2 × 10(-4)), and remained significant after permutation-based multiple corrections (P(c) value: combined=0.0013). After accounting for the effect of rs168449, we identified another significant single nucleotide polymorphism (rs1435520), suggesting a second independent signal regulating serum PF4 levels (conditional P value: African Americans=0.02, whites=0.02). Together, these single nucleotide polymorphisms explained 0.98% and 1.23% of serum PF4 variance in African Americans and whites, respectively. Additionally, in African Americans, we found an additional PF4 variant (rs8180167), uncorrelated with rs168449 and rs1435520, associated with serum tumor necrosis factor-α levels (P=0.008, P(c)=0.048). CONCLUSIONS: Our study highlights the importance of PF4 variants in the regulation of platelet activation (PF4) and systemic inflammation (tumor necrosis factor-α) serum biomarkers.

Internal growth of nonsolid lung nodules: radiologic-pathologic correlation.

PURPOSE: To determine whether computed tomographic (CT) attenuation values correlate with the histologic measurements of a lung cancer manifesting as a nonsolid nodule and to quantify the extent to which the tumor replaces the airspace within the nodule. MATERIALS AND METHODS: Informed consent was obtained to analyze images from CT and pathologic examination under an institutional review board-approved protocol. Fifteen patients who had undergone resection of nonsolid lung cancer were evaluated. On the basis of the CT attenuation values of nonsolid nodules, nonneoplastic lung, soft tissue, and air, the overall proportion of soft tissue in the nodule and nonneoplastic lung and the difference between these two measures were calculated. The analogous measures were obtained from a representative digitized histologic slide. The area of each nodule and the proportion of air within it were measured, and the proportion of soft tissue in the nodule and nonneoplastic lung and the difference between the two were calculated. The difference between the two proportions at CT and histologic examination are the proportions attributable to the cancer on the basis of CT and histologic examinations, respectively. Linear regression was performed to assess the relationship between these measures. RESULTS: The average proportions of soft tissue in the nodule at CT and histologic examination were 48% and 69%, respectively, and they showed significant correlation with each other (P = .02); in addition, each showed significant correlation with the attenuation of the nodule (P < .0001 and P = .02, respectively). The difference between the proportions of soft tissue in nodule and nonneoplastic lung at CT and histologic examination were 37% and 30%, respectively, and both were independent of the tumor diameter (P = .26 and P = .41). CONCLUSION: The proportion of soft tissue within a nonsolid nodule is correlated with attenuation at CT. This allows for measurement of change within the nodule. An increase of 100 HU in nodule attenuation represents an approximately 10% increase in tumor volume.

Postmenopausal hormone therapy and ductal carcinoma in situ: a population-based case-control study.

BACKGROUND AND AIM: The relationship between hormone therapy (HT) and invasive breast cancer has been extensively investigated, but the relationship between HT and in situ breast cancer has received relatively little attention. We examined the relationship between HT and ductal carcinoma in situ (DCIS) among postmenopausal women who participated in a population-based case-control study in Connecticut, USA. METHODS: This analysis included 1179 post-menopausal women (603 controls and 576 cases), who comprised a subset of a population-based case-control study that included all incident cases of breast carcinoma in situ (BCIS) in Connecticut and frequency-matched controls by 5-year age intervals. RESULTS: We found no association between DCIS and ever use of any HT (adjusted odds ratio (OR)=0.85, 95% confidence interval (CI): 0.65-1.11); of estrogen alone (adjusted OR=0.93; 95% CI: 0.68-1.29) or of estrogen and progesterone (adjusted OR=0.75; 95% CI: 0.52-1.08). There was also no association between DCIS and current use of these hormones. In addition, estimated risk of DCIS did not increase with duration of use of these preparations. CONCLUSIONS: These results add to a small literature that remains inconclusive. To determine whether HT poses risk of in situ breast cancer, larger studies with greater power and precise control of important covariates (e.g., mammography screening) are needed, as are meta-analyses of available data.

Zone of transition: a potential source of error in tumor volume estimation.

PURPOSE: To measure the width of the zone of transition (ZOT) between nonaerated solid tumor and surrounding nonneoplastic lung parenchyma and determine the extent to which ZOT influences computer-derived estimates of tumor volume based on computed tomographic (CT) images. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional research board. The histologic slide containing the maximum tumor area was digitized for 20 consecutive patients with solid adenocarcinoma. The outer border of the tumor (A2) was marked; it included all lung parenchyma having any tumor cells. The inner border of the tumor (A1) was marked; it included only solid tumor where lung parenchyma was no longer preserved. Assuming two circles with areas of A2 and A1, the corresponding two radii, R2 and R1, were calculated. The average width of the ZOT was defined as R2 minus R1. The relationship between ZOT and tumor diameter on the CT images prior to surgery was assessed by using regression analysis. The relationship between ZOT and tumor volume was assessed by using a theoretical model of idealized spheres with varying diameters. RESULTS: The mean width of the ZOT was 0.78 mm (median, 0.48 mm). The proportional effect of ZOT on tumor volume estimates decreased with increasing tumor diameter and increased with increasing width of ZOT. Correlation between ZOT and tumor diameter was not significant (P = .87). CONCLUSION: The average width of ZOT is about a single pixel width on a full field of view CT scan; thus, the ZOT can have a large effect on volume estimates, particularly for small tumors.

Variation in vascular distribution in small lung cancers.

PURPOSE: To assess the vascular component of small lung cancers. MATERIAL AND METHODS: We identified 105 resected non-small-cell lung carcinomas without pathologic evidence of vascular, lymphatic, bronchial, or pleural invasion. The percentage of BAC (% BAC) of all adenocarcinomas was determined by a pulmonary pathologist. A representative histology slide of each carcinoma was digitally scanned and the number of blood vessels (#V) with at least a diameter of 200microm was identified as well as the area of these blood vessels (VA) and of the tumor (TA) was obtained. The CT consistency of the cancers was also recorded as non-solid (NS), part-solid (PS) and solid. RESULTS: The number of blood vessels per cm(2) of tumor area (#V/TA) was higher for adenocarcinoma (7.3+/-4.7) as compared with large- and squamous-cell carcinoma (3.6+/-2.1, 2.3+/-1.1, respectively, P<0.0001). For adenocarcinoma, #V/TA decreased with decreasing % BAC from 10.3 vessels per cm(2) of tumor area for 100% BAC to 5.1 vessels per cm(2) of tumor area for 0% BAC. The ratio of the total vascular area to tumor area (VA/TA), however, did not differ significantly by cell type nor for the adenocarcinoma by % BAC (P=0.87). While #V/TA decreased from 9.6 for non-solid nodules, to 7.5 for part-solid nodules and to 5.1 for solid nodules, there was no significant difference (P=0.27) in the VA/TA ratio by nodule consistency. Overall, VA comprised 2.7% of the total tumor area (TA) for 105 cancers. CONCLUSIONS: These results suggest that tumor vessels experience a continuous temporal and spatial remodeling as tumors grow and that bigger tumors tend to have fewer but larger blood vessels. It also suggests that, on average, squamous- or large-cell carcinomas have a larger average vessel diameter as compared with adenocarcinomas and that the vasculature of an adenocarcinoma might remodel as the % BAC decreases. The overall proportion of tumor volume comprised of vessels 200microm or larger is small and unlikely to influence overall tumor volume and doubling time estimates.

Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: histopathologic features and their prognostic implications.

PURPOSE: To study the histopathologic features of CT screen-detected Stage IA adenocarcinomas to determine whether survival differed by the proportion of bronchioloalveolar component (BAC) or by the presence of multiple lesions in node-negative patients. METHODS: Five pathologists with expertise in pulmonary pathology examined 279 resected cases of adenocarcinomas, 30 mm or less in length diagnosed by CT screening for lung cancer. The panel determined the consensus diagnosis for each case, identified additional cancers, and classified each case as solitary or non-solitary. The presence and proportion of BAC was also documented. RESULTS: Of the cases of adenocarcinoma, 20 (7%) were BAC subtype, 246 (88%) mixed subtype and 13 (5%) adenocarcinoma-OTHER. BAC cases manifested as non-solid and part solid nodules, mixed as solid and part-solid, and other as solid only. Kaplan-Meier 10-year survival rates were 100% for BAC and adeno-MIXED with 90-99% BAC cases, 95% for mixed with 1-90% BAC, 90% for those without a BAC component, and 75% for other cases. Fifty (18%) cases were non-solitary carcinomas and 44 of these were node negative; the non-solitary node-negative cases had the same excellent prognosis as solitary node-negative cases. CONCLUSIONS: The proportion of BAC component was a positive prognostic factor and correlated with CT consistency. Contrary to staging predictions, cases of non-solitary node-negative adenocarcinoma had the same excellent prognosis as solitary node-negative cases, suggesting that most of the small, node-negative multiple carcinomas probably represent multiple primaries rather than intrapulmonary metastasis.

Comparison of pathologic findings of baseline and annual repeat cancers diagnosed on CT screening.

Screening for lung cancer produces two groups of lung cancers. Baseline cases include all prevalent cases with the expectation that slower-growing cancers and those that have achieved higher stage will be found in greater frequency. Repeat examination is expected to detect those cancers which have crossed the threshold for detection during the screening interval - 1 year in this study - and these are typically more rapidly growing cancers. The two groups encompass the full spectrum of lung cancers. Comparison of the baseline and annual repeat cases revealed differences in types of lung cancer. There were 202 baseline-detected cancers spanning the spectrum of pulmonary neoplasms with some slowly growing, some rapidly progressive and some at high stage; the 48 annual repeat cancers also included a spectrum of lung cancers but with more of the rapidly growing types, and more closely approximated the clinical spectrum of lung cancers. The NE carcinomas showed this trend best; small-cell carcinomas were under-represented and typical carcinoids were only found in the baseline group. Repeat cancers were found to grow rapidly, were typically smaller, less often multiple and the adenocarcinomas were less often pure BAC and less frequently contained a BAC component when invasive. The baseline adenocarcinomas included most of the BAC's, which is a diagnosis that requires special attention to its WHO definition. AAH was found to be frequently associated with adenocarcinoma, particularly BAC. Both baseline and annual repeat cases had a high percentage of invasive carcinomas with comparably high rates of resectability, high rates of node negativity and consequently a high proportion of cases in low stage.

Quality of life for women diagnosed with breast carcinoma in situ.

PURPOSE: Limited data exist on long-term quality of life (QOL) for women diagnosed with breast carcinoma in situ (BCIS). PARTICIPANTS AND METHODS: The data are on 795 BCIS participants diagnosed among female residents of Connecticut from September 15, 1994 to March 14, 1998, and 702 controls frequency-matched to the case participants by 5-year age intervals and geography. These women were participants in a large, population-based case/control study and subsequent follow-up study. Telephone interviews at follow-up were used to collect data on QOL at 5 years from initial diagnosis or contact, using the Medical Outcomes Study, Center for Epidemiologic Studies-Depression, and CAGE (Cut down, Annoyed, Guilty, Eye-opener) alcohol consumption scales. QOL outcomes were compared by case/control status and by case treatment group: lumpectomy, lumpectomy with adjuvant radiation therapy, and mastectomy. RESULTS: At 5 years after diagnosis, women diagnosed with BCIS report levels of physical, emotional, and mental health functioning similar with those reported in a general healthy female population. Case participants and controls did not differ in reported levels of limitations due to physical health problems, bodily pain, social functioning, or overall physical functioning. Case participants who underwent lumpectomy with radiation reported lower levels of emotional functioning, general health perceptions, vitality, sexual interest, and overall mental health, as well as more depressive symptoms than did control subjects; although, the clinical significance of these statistical differences appears to be limited. CONCLUSION: At 5 years after treatment, women diagnosed with BCIS report good physical and emotional functioning relative to control populations.

Postchemotherapy MRI overestimates residual disease compared with histopathology in responders to neoadjuvant therapy for locally advanced breast cancer.

UNLABELLED: The utility of breast magnetic resonance imaging in patients receiving neoadjuvant chemotherapy is not well defined. We compared serial magnetic resonance imaging examinations with histologic posttreatment examinations in patients treated with primary chemotherapy for locally advanced breast cancer. PATIENTS AND METHODS: Eligible patients with locally advanced breast cancer received doxorubicin 60 mg/m(2) and docetaxel 60 mg/m(2) (with granulocyte colony stimulating factor support) every 14 days for a maximum of six cycles. Breast magnetic resonance imaging was performed at baseline and repeated every two cycles. Surgery (either local excision or mastectomy) was performed after six cycles in responding or stable patients. Residual tumor size on pathology and preoperative magnetic resonance imaging was compared; concordance was defined as a < or = 0.5-cm difference. RESULTS: To date, three of 17 enrolled subjects (17.6%) attained pathologic complete response, and three additional patients attained near pathologic complete response, with residual foci of < or = 1 mm. Of these six patients, only one was disease-free by magnetic resonance imaging. Discordance between magnetic resonance imaging findings and pathologic evaluation was found in four of six patients (66.6%) who obtained pathologic complete response or near pathologic complete response. In the three patients in whom four axillary lesions were followed with magnetic resonance imaging, discordance was found in all four lesions, with magnetic resonance imaging overestimating pathologic disease in all cases. DISCUSSION: Our findings caution that magnetic resonance imaging may frequently overestimate residual invasive carcinoma after neoadjuvant chemotherapy. These results contradict previous studies suggesting that postchemotherapy magnetic resonance imaging may underestimate residual cancer. The use of magnetic resonance imaging in evaluating response to therapy in locally advanced breast cancer should be further studied.

Pathologic findings of lung tumors diagnosed on baseline CT screening.

Sixty-five people had a resection of their baseline screen-diagnosed lung cancers in the Early Lung Cancer Action Program. Forty-nine of the carcinomas were solitary, and 42 of these were adenocarcinomas. More than 1 carcinoma was found in 16 patients after pathologic examination of the lobectomy specimen; 15 of the 16 second carcinomas were adenocarcinomas, mixed subtype. Eighteen cases were submitted by local pathologists as Bronchioloalveolar carcinomas but were found to be invasive adenocarcinomas according to the World Health Organization classification by the Pathology Review Panel. Of the 65 resected cases, 57 were N0, 7 were N1, and 1 was N2. Upon careful review of the lobectomy specimens, 49 cases had solitary malignancies, 30 were Stage IA, 13 Stage IB, 3 Stage IIA, 2 Stage IIB, and 1 Stage IIIA on the basis of the American Joint Committee on Cancer/International Union for Cancer Control criteria. In the 16 cases found to have multiple malignancies, 6 had histologically different carcinomas and the remaining 10 had histologically identical malignancies. Eighty-three percent (76/92) of the carcinomas invaded the stroma with destruction of normal lung, and 21% (19/92) also showed either pleural or angiolymphatic invasion, even though 88% (57/65) of the carcinomas were free of lymph node metastases. This report describes the pathologic findings of the resected cases. Histopathologic distinctions among atypical adenomatous hyperplasia, bronchioloalveolar carcinomas, and invasive adenocarcinoma are described in detail.

Characterization of an anti-lymphocyte function-associated antigen-1 antibody in a simian immunodeficiency virus-pig-tailed macaque (Macaca nemestrina) model.

The simian immunodeficiency virus (SIV)/pig-tailed macaque (Macaca nemestrina) model of acquired immune deficiency syndrome (AIDS) is a powerful system in which to study cell adhesion molecules and retroviral pathogenesis in vivo. Preliminary experiments were conducted to examine the role of lymphocyte function-associated antigen 1 (LFA-1) in early SIV infection in vivo by using an LFA-1 monoclonal antibody (MHM.23) specific to human LFA-1. In vitro studies revealed that at concentrations of > or = 20 microg/ml, MHM.23 blocked LFA-1-mediated adhesion and T-cell activation (>90%) of pig-tailed macaque peripheral blood mononuclear cells (PBMCs). In addition, SIVmac239 infection of macaque cells was inhibited in a dose-dependant manner by MHM.23. Administration of MHM.23 to pig-tailed macaques inhibited LFA-1-ICAM-1-mediated activity in vivo and maintained binding on macaque cells for < or = 4 d. Our in vitro studies indicated that at an MHM.23 concentration of 20 microg/ml, macaque PBMCs were completely saturated. Our in vivo studies determined that 5 mg/kg MHM.23 intravenously every 24 h was required to maintain saturating levels and inhibit LFA-1-ICAM-1 function in pig-tailed macaques.

Immunohistochemical biomarkers in patients with early-onset breast carcinoma by tissue microarray.

UNLABELLED: Young women with breast cancer have a poor prognosis, and the role of biologic markers in young women is not well defined. We investigated the association of estrogen receptor, progesterone receptor, Bcl-2, HER-2/neu, p53, and Ki-67 with clinicopathologic features and outcome in young women with breast cancer. METHODS: A cohort of 103 patients with early-onset breast cancer treated with conservative surgery and radiotherapy were entered in this study. Age range was 25-45 years, and median follow-up was 8.7 years. Each of the paraffin-embedded specimens was immunologically stained for six biomarkers expression by a recently developed tissue microarray method. RESULTS: The 10-year overall breast relapse-free and distant relapse-free survival rates were 82.7%, 84.6.4%, and 66.7%, respectively, with 14 local relapses and 26 distant metastases among the 103 patients evaluated. Positive expression of estrogen receptor, progesterone receptor, bcl-2, HER-2/neu, p53, and Ki-67 were 42.7%, 48.5%, 35.6%, 28.0%, 36.9%, and 39.7%, respectively. Tumor stage and nodal status were significantly associated with overall survival and distant metastasis-free rate in univariate and multivariate analysis. Progesterone receptor negativity and Ki-67 positivity were associated with distant metastasis. There was no statistically significant correlation between the six biomarkers and local relapse. CONCLUSIONS: Progesterone receptor, Ki-67, tumor stage, and nodal status were prognostic factors for distant failure in early-stage breast cancer in young patients. Further studies are needed to find other biologic markers associated with local failure in this group of patients.

Phosphorylated/activated HER2 as a marker of clinical resistance to single agent taxane chemotherapy for metastatic breast cancer.

Purpose. To determine the association of phosphorylated/activated HER2 (P-HER2) and response to taxane chemotherapy in patients with metastatic breast cancer (MBC). Materials and Methods. Archived tumor specimens of patients with MBC treated on clinical trials with taxane monotherapy were analyzed by immunohistochemistry (IHC) for the presence of phosphorylated HER2 using the PN2A monoclonal antibody. Chi-squared analysis was performed to evaluate the association of P-HER2 status and efficacy of single agent taxane therapy. Results. One hundred twenty-six cases were identified as evaluable for both IHC and clinical outcome. Twelve cases (10 percent) were positive for P-HER2, of which 5 had evidence of clinical progression and 7 had evidence of clinical benefit with taxane therapy. Of the 114 cases that were negative for P-HER2, 20 demonstrated progression and 94 had clinical benefit. Chi-squared analysis revealed a significant correlation between the presence of P-HER2 and resistance to taxane therapy, chi2 = 3.9724 and p = 0.046. Conclusions. Phosphorylated/activated HER2 is associated with clinical resistance to single agent taxane therapy for MBC. The likelihood of direct progression of disease on taxane was greater in cases of PN2A-positive tumors (42 percent) as opposed to PN2A-negative ones (18 percent, p = 0.046). Functional assessment of HER2 status may provide unique predictive information not seen with conventional assessments.

Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ.

CONTEXT: The distribution of BRCA1 and BRCA2 mutations in women diagnosed with noninvasive breast carcinoma is unknown. OBJECTIVE: To estimate the BRCA1 and BRCA2 mutation prevalence in women with ductal carcinoma in situ (DCIS), unselected for age, family history, or ethnicity. DESIGN, SETTING, AND PARTICIPANTS: The data were 369 DCIS cases diagnosed among female residents aged 20 to 79 years from the state of Connecticut between September 15, 1994, and March 14, 1998. These women were participants in a large population-based case-control study of breast carcinoma in situ. Telephone interviews were used to collect risk factor information and blood or buccal specimens were collected for BRCA1 and BRCA2 mutation testing. MAIN OUTCOME MEASURES: Prevalence of disease-associated mutations of BRCA1 and BRCA2 in women diagnosed with DCIS. RESULTS: Three (0.8%) and 9 (2.4%) of 369 DCIS cases had disease-associated mutations in BRCA1 or BRCA2, respectively. One woman had a mutation in both genes (BRCA1 W321X and BRCA2 3398del5). Carriers were significantly more likely than noncarriers to report a first-degree (mother, sister, or daughter) family history of breast cancer (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.1-12.4), as well as a personal history of ovarian cancer. In addition, carriers were more likely than noncarriers to be diagnosed at an early age (<50 years) (OR, 3.4; 95% CI, 1.0-11.7), as well as to report at least 1 first-degree relative diagnosed with breast cancer before 50 years (OR, 10.6; 95% CI, 3.0-37.0). CONCLUSIONS: Ductal carcinoma in situ is a part of the breast/ovarian cancer syndromes defined by BRCA1 and BRCA2, with mutation rates similar to those found for invasive breast cancer. These findings suggest that patients with breast cancer with an appropriate personal or family history of breast and/or ovarian cancer should be screened and followed according to high-risk protocols, regardless of whether they are diagnosed with in situ or invasive breast cancer.

Incidence of BRCA1 and BRCA2 mutations in young Korean breast cancer patients.

PURPOSE: The prevalence of BRCA-associated breast carcinoma in the Korean population has not been evaluated extensively. METHODS: Sixty Korean women who developed breast cancer by age 40 years were studied. Lymphocyte specimens from peripheral blood were processed for BRCA1 and BRCA2 by complete sequencing. Family history through three generations was obtained. Available paraffin-embedded tissue blocks were processed for immunohistochemical staining. RESULTS: In the cohort of 60 patients, nine patients with 11 deleterious mutations (six in BRCA1 and five in BRCA2) and seven missense mutations of unknown significance were found. Two patients had deleterious mutations in both BRCA1 and BRCA2 (double mutant). One half of the mutations were novel, and no founder mutations were observed in this cohort. Most of the BRCA-associated patients had no family history of breast and/or ovarian cancer. The expression of HER-2/neu, cyclin D1, and hormone receptors was less common, and p53 overexpression was more common in BRCA-associated tumors. CONCLUSION: The prevalence of BRCA1 and BRCA2 mutations in Korean women with breast cancer at a young age was high. However, the penetrance, as evidenced by the low frequency of breast and ovarian cancers in family members, appears to be low. These data suggest that there may be different genetic and etiologic factors affecting transmission and penetrance of the BRCA genes in Korean patients with breast cancer diagnosed at a young age.

Molecular markers for prognosis after isolated postmastectomy chest wall recurrence.

BACKGROUND: Local chest wall recurrence after mastectomy occurs in 10-20% of patients with operable breast carcinoma. The objective of the current study was to assess the prognostic value of molecular markers at the time of local recurrence and to compare these markers with clinical variables. METHODS: Between 1975 and 1999, the authors treated 113 patients at their institution for postmastectomy chest wall recurrences with full-course external beam radiotherapy. Patients who presented primarily with lymph node recurrences or with simultaneous distant metastasis were excluded. Follow-up from the time of chest wall recurrence was 10.13 years. All clinical and pathologic data from the original diagnosis and from the time of chest wall recurrence were entered into a computerized database. Paraffin-embedded tumor specimens from the chest wall recurrences were available for 43 patients and were constructed into tissue microarrays for immunohistochemical staining of estrogen receptor, progesterone receptor (PR), p53, HER-2/neu, and cyclin D. RESULTS: Overall survival after chest wall recurrence for the entire cohort was 46% at 5 years and 28% at 10 years. The distant metastasis-free survival rate was 49% at 5 years and 40% at 10 years. Local-regional control of disease was achieved in 79% of patients at 10 years. In multivariate analysis, significant factors for distant metastasis after local recurrence were time to recurrence (< 2 years from the original diagnosis to chest wall recurrence) and PR status (distant metastasis-free survival rate: 84% [PR-positive] vs. 38% [PR-negative]; P = 0.007). The only significant factor for local-regional disease progression was HER-2/neu status. Patients with positive HER-2/neu status had a local-regional progression-free rate of 59%, compared with 92% for patients with negative HER-2/neu status. CONCLUSIONS: The prognosis for patients after local-regional recurrence of breast carcinoma is relatively poor. Longer time to local recurrence and positive PR status were associated with favorable distant metastasis-free rates and long-term survival. Positive HER-2/neu status was associated with poorer local-regional control of disease. Implications for systemic therapy and further studies are discussed.

The risk of a contralateral breast cancer among women diagnosed with ductal and lobular breast carcinoma in situ: data from the Connecticut Tumor Registry.

BACKGROUND: Women diagnosed with breast carcinoma in situ are at increased risk for developing a contralateral breast cancer. The magnitude of this risk and the relationship between this risk and age, time since diagnosis, histologic subtype, and treatment for the first breast cancer is continuing to be defined. METHODS: The risk of developing a contralateral breast cancer is examined among 4198 women diagnosed with breast carcinoma in situ and reported to the Connecticut Tumor Registry (CTR) between January 1, 1975 and March 14, 1998 using Kaplan-Meier estimation. A Cox proportional hazards model is used to assess the effect of surgical treatment, radiation therapy, age at diagnosis, race, histology, marital status, anatomic location within the breast, and time since diagnosis upon this risk. RESULTS: The cumulative 5- and 10-year probabilities of being diagnosed with a contralateral breast cancer among women initially diagnosed with a ductal breast carcinoma in situ (DCIS) were 4.3% (95% confidence interval, 3.6-5.0%) and 6.8% (95% confidence interval, 5.5-8.2%), respectively. These risks are 3.35 times greater than those for women without a history of breast cancer but are similar to those for women diagnosed with non-metastatic invasive ductal carcinomas of the breast. The cumulative 5- and 10-year probabilities of being diagnosed with a contralateral breast cancer among women initially diagnosed with a lobular breast carcinoma in situ (LCIS) were 11.9% (95% confidence interval, 9.5-14.3%) and 13.9% (95% confidence interval, 11.0-16.8%), respectively. CONCLUSIONS: Women diagnosed with LCIS were 2.6 (95% confidence interval, 2.0-3.4%) times more likely than women with DCIS to be diagnosed with a contralateral breast cancer within the first six months of the first breast primary. The risk of developing a contralateral breast cancer more than 6 months after the initial breast cancer was independent of surgical or radiation therapy, time since diagnosis, age at diagnosis, histology, race, marital status, or anatomic location of the cancer within the breast.

A comparison of five immunohistochemical biomarkers and HER-2/neu gene amplification by fluorescence in situ hybridization in white and Korean patients with early-onset breast carcinoma.

BACKGROUND: The objective of this article was to compare five tumor markers between white women in the U.S. and native Korean women with early-onset breast carcinoma. METHODS: Sixty Korean women who were diagnosed with breast carcinoma at age 45 years or younger and 60 white women with breast carcinoma who were matched by age were selected for this study. The median age of both groups was 37 years. Paraffin embedded blocks of the primary tumor were processed for immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR), p53, cyclin D1, and HER-2/neu. RESULTS: The proportion of tumors that stained positive for ER, PR, p53, and cyclin D1 in the Korean women were 47.5%, 42.4%, 28.8%, and 40.9%, respectively; in the white women, the proportions were 43.9%, 52.6%, 21.1%, and 59.1%, respectively. The differences between the white patients and the Korean patients were not statistically significant with respect to any of those variables. A significant difference was found in the expression of HER-2/neu. Specifically, positive HER-2/neu status was observed in 47.5% of Korean women, compared with overexpression in only 15.8% of white women (P < 0.001). Fluorescence in situ hybridization analysis for HER-2/neu gene amplification on all HER-2/neu positive samples that scored 2 + and 3 + demonstrated a significant difference (P = 0.007) in gene amplification between the two populations. Differences in HER-2/neu positivity were observed for the entire cohort as well as among the subsets of patients with negative and positive lymph node status. No association was found between immunoreactivity for the five markers and axillary lymph node metastasis. CONCLUSIONS: The findings of high positivity of HER-2/neu expression and gene amplification in Korean women with early-onset breast carcinoma may have potential implications for local and systemic management of breast carcinoma, especially anti-HER-2/neu therapy for patients with hormone receptor negativity. Further research will be needed to identify biologic and genetic factors and their effects on the survival between different racial groups.