Early and more advanced unifocal and multifocal breast carcinomas and their molecular phenotypes

Background

I examined the relationship between the recently established prognostic parameter, molecular tumor phenotype and tumor size, lesion distribution (unifocal, multifocal, diffuse growth), and lymph node status.

Materials and Methods

I analyzed 660 consecutive invasive breast carcinomas documented in large-format histology sections. Immunohistochemistry was used to phenotype the tumors on the basis of estrogen and progesterone receptor expression, HER2 (human epithelial growth factor receptor 2) overexpression, and expression of basal markers.

Results

The proportion of luminal A tumors (84.8% vs. 71.6%; P < .0001) and basal-like tumors (5.0% vs. 14.8%; P < .0001) were significantly different in early (<15 mm) and more advanced invasive breast carcinomas, whereas the proportion of luminal B and HER2 type tumors (4.2% vs. 7.8%, and 5.7% vs. 4.8%, respectively) were not. All the phenotypes had similar percentages of multifocal tumors, whereas most diffuse invasive carcinomas were luminal A type. Early luminal A carcinomas had significantly fewer lymph node metastases (LNM) than more advanced carcinomas but luminal B and HER2 type tumors showed no such difference. This difference was evident (15.4% vs. 42.4%) but statistically not significant in the basal-like category. Multifocal tumors of all phenotypes had significantly higher frequencies of LNM compared with unifocal tumors.

Conclusion

Multifocality of the invasive component represents a negative prognostic parameter associated with significantly increased LNM in all phenotype, whereas larger tumor size was such a parameter only in the luminal A category. HER2 overexpression occurs early in the natural history of tumors and is associated with high LNM rates.     

Immunohistochemical surrogate markers of breast cancer molecular classes predicts response to neoadjuvant chemotherapy

BACKGROUND:

Complete pathologic response to neoadjuvant chemotherapy (NACT) is predominantly seen in “ERBB2” and “basal‐like” tumors using expression profiling. We hypothesize that a similar response could be predicted using semiquantitative immunohistochemistry for estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2).

METHODS:

ER, PR, and HER2 were used to classify 359 tumors treated with NACT into 6 groups: luminal A (strong ER+, HER2 negative), luminal B (weak to moderate ER+, HER2 negative), triple negative (negative for ER, PR, and HER2), ERBB2 (negative for ER and PR, but HER2+), luminal A‐HER2 hybrid (strong ER+ and HER2+), and luminal B‐HER2 hybrid (weak to moderate ER+ and HER2+). Complete pathologic response was defined as absence of invasive carcinoma in the breast and regional lymph nodes.

RESULTS:

Thirteen percent (48 of 359) demonstrated complete pathologic response. The highest rate of complete pathologic response was seen in ERBB2 (33%; 19 of 57) and triple negative (30%; 24 of 79) tumor classes. Among the ER+ “molecular” group, the highest rate of complete pathologic response was seen among luminal B‐HER2 hybrid tumors, 8% (2 of 24). Remainder of ER+ tumors demonstrated a very low rate of complete pathologic response, 1.5% (3 of 198). The 5‐year survival for patients achieving complete pathologic response was 96% compared with 75% in patients that failed to achieve complete pathologic response. The overall survival was worse in the ER‐negative group (ERBB2 and triple negative) compared with the ER‐positive group.

CONCLUSIONS:

We confirm the recently defined “triple negative paradox,” or rather “hormone receptor negative paradox,” that despite the best response to NACT, ERBB2 and triple negative tumors show the worst overall survival because of higher relapse among those with residual disease. Cancer 2010. © 2010 American Cancer Society.     

Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancer

Introduction

At least four major categories of invasive breast cancer that are associated with different clinical outcomes have been identified by gene expression profiling: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) and basal-like. However, the prevalence of these phenotypes among cases of ductal carcinoma in situ (DCIS) has not been previously evaluated in detail. The purpose of this study was to compare the prevalence of these distinct molecular subtypes among cases of DCIS and invasive breast cancer.

Methods

We constructed tissue microarrays (TMAs) from breast cancers that developed in 2897 women enrolled in the Nurses' Health Study (1976 to 1996). TMA slides were immunostained for oestrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin 5/6 (CK5/6) and epidermal growth factor receptor (EGFR). Using these immunostain results, cases were grouped into molecularly defined subtypes.

Results

The prevalence of the distinct molecular phenotypes differed significantly between DCIS (n = 272) and invasive breast cancers (n = 2249). The luminal A phenotype was significantly more frequent among invasive cancers (73.4%) than among DCIS lesions (62.5%) (p = 0.0002). In contrast, luminal B and HER2 molecular phenotypes were both more frequent among DCIS (13.2% and 13.6%, respectively) as compared with invasive tumours (5.2% and 5.7%, respectively) (p < 0.0001). The basal-like phenotype was more frequent among the invasive cancers (10.9%) than DCIS (7.7%), although this difference was not statistically significant (p = 0.15). High-grade DCIS and invasive tumours were more likely to be HER2 type and basal-like than low- or intermediate-grade lesions. Among invasive tumours, basal-like and HER2 type tumours were more likely to be more than 2 cm in size, high-grade and have nodal involvement compared with luminal A tumours.

Conclusion

The major molecular phenotypes previously identified among invasive breast cancers were also identified among cases of DCIS. However, the prevalence of the luminal A, luminal B and HER2 phenotypes differed significantly between DCIS and invasive breast cancers.     

Clinical relevance of the distribution of the lesions in 500 consecutive breast cancer cases documented in large-format histologic sections

BACKGROUND: Breast carcinoma is a heterogeneous group of diseases deviating from each other not only in their clinical manifestations and outcome but also in their histologic appearance. The submacroscopic morphology of breast carcinomas, the distribution of the lesions, and the extent of the disease are seldom studied. Even more infrequently are these parameters included in surgical pathology reports. Conversely, the routine use of large-format histologic sections in workup of operated breast specimens provides better insight into the significance of these parameters. The aim of the study was to identify breast carcinoma growth patterns indicating increased metastatic potential of the tumor and a need for more aggressive therapy. METHODS: In all, 500 consecutive breast cancer cases, all of which were documented on large-format histologic sections, were retrospectively analyzed. The distribution of both in situ and invasive components of the tumors (unifocal/multifocal/diffuse) was defined, determined, and compared with the type of surgical intervention performed and the frequency of ipsilateral lymph node metastasis as endpoints. The extent of the disease, the size of the tumor, the presence or absence of lymphovascular invasion (LVI), and the proportion of invasive lobular carcinomas in the categories with different distributions were also analyzed. RESULTS: Only 34% of the analyzed cases could be categorized as unifocal. This kind of tumor distribution was associated with lymph node metastasis in 28% of the cases, with LVI in 18%, with breast-conserving surgery in 67%, and with a proportion of 4% invasive lobular carcinomas. Tumors with a unifocal invasive component upgraded to multifocal or diffuse because of the distribution of the associated in situ component had similar characteristics. With their larger extent, tumors with a diffuse in situ component required mastectomy in 43% of cases. Multifocal distribution of the invasive component in the tumors was associated with higher frequency of LVI (42%) and lymph node metastases (48%), with a substantially lower number of cases undergoing breast-conserving surgery (33%) and with a higher proportion of lobular carcinomas (25%). If the multifocal invasive foci were associated with a diffuse in situ component, the proportion of invasive lobular carcinomas was only 5%. The extent of the lesions (defined as the area of breast tissue involved by in situ, invasive, and/or intravascular tumor foci) was >or=2 cm in >90% of multifocal cases and >or=4 cm in >70%. Diffusely growing invasive carcinomas were rare (only 20 cases), but were associated with lymph node metastasis in 60% of cases and resulted in mastectomy in 85% of the cases. Approximately two-thirds (65%) of these tumors belonged to invasive lobular carcinomas. The extent of diffusely growing invasive carcinomas was >or=4 cm in 75% of the cases. Although LVI was detected in only 10% of tumors with a diffusely growing invasive component, such tumors were found to have lymph node metastasis significantly more often (odds ratio of 2.33) and required mastectomy much more frequently (odds ratio of 2.58) compared with purely unifocal breast carcinomas. CONCLUSIONS: These results indicate that the distribution of invasive and in situ tumor structures in breast carcinomas as defined in the current study, together with the extent of disease, are important morphologic parameters which determine the required surgical intervention and are related to biologic factors such as metastatic capacity. The method of large-section histology allows the examiner to properly document and demonstrate these important parameters, thus facilitating understanding of their clinical relevance.     

Disruption of the blood brain barrier by brain metastases of triple‐negative and basal‐type breast cancer but not HER2/neu‐positive breast cancer

BACKGROUND:

Generally, the blood‐brain barrier (BBB) of brain metastasis was thought to be disrupted.

METHODS:

We retrospectively performed immunohistochemical staining for glucose transporter 1 (GLUT1) and breast cancer resistance protein (BCRP) to evaluate the status of the BBB in resected brain metastases. Associations between expression of GLUT1 and/or BCRP and the immunohistochemical profiles of breast cancers, such as the statuses of hormone receptors, human epidermal growth factor receptor 2 (HER2/neu), and a basal‐type marker (cytokeratin 5/6, HER1), were also analyzed.

RESULTS:

The study included 29 breast cancer patients with brain metastasis who had undergone brain tumor resections. Among the 29 patients, there was no expression of GLUT1 and BCRP in the intratumor microvessels of 9 (32%) and 11 (38%) patients, respectively. There was no expression of both GLUT1 and BCRP in 8 patients (28%). The expression of GLUT1 was significantly associated with that of BCRP (P < .001). A positive correlation was observed between the expression of GLUT1 and/or BCRP and brain metastases of HER2/neu‐positive breast cancer (P = .012), while a negative correlation was observed between the expression of GLUT1 and/or BCRP and brain metastases of triple negative or basal‐type breast cancer (P = .014 and P = .003 for triple negative and basal‐type, respectively).

CONCLUSIONS:

Brain metastases of triple negative or basal‐type breast cancers may often disrupt the BBB, whereas brain metastases of HER2/neu‐positive breast cancer tend to preserve the BBB. Cancer 2010. © 2010 American Cancer Society.     

Molecular Phenotype of Breast Cancer According to Time Since Last Pregnancy in a Large Cohort of Young Women

Background.

The increase in breast cancer risk during pregnancy and postpartum is well known; however, the molecular phenotype of breast cancers occurring shortly after pregnancy has not been well studied. Given this, we investigated whether nulliparity and the time interval since pregnancy among parous women affects the breast cancer phenotype in young women.

Materials and Methods.

We examined molecular phenotype in relation to time since pregnancy in a prospective cohort of 707 young women (aged ≤40 years) with breast cancer. Parity was ascertained from study questionnaires. Using tumor histologic grade on central review and biomarker expression, cancers were categorized as luminal A- or B-like, HER2 enriched, and triple negative.

Results.

Overall, 32% were luminal A-like, 41% were luminal B-like, 9% were HER2 enriched, and 18% were triple negative. Although, numerically, patients diagnosed >5 years after pregnancy had more luminal A-like subtypes than women with shorter intervals since pregnancy, there was no evidence of a relationship between these intervals and molecular subtypes once family history of breast cancer and age at diagnosis were considered.

Conclusion.

Distribution of breast cancer molecular phenotype did not differ significantly among young women by parity or time interval since parturition when important predictors of tumor phenotype such as age and family history were considered.

Implications for Practice:

Distribution of breast cancer molecular phenotype did not differ among parous young women by time interval since pregnancy. The implication of these findings for clinical practice suggests that pregnancy-associated breast cancers may be seen up to 5 years beyond parturition.     

GATA-3 is superior to GCDFP-15 and mammaglobin to identify primary and metastatic breast cancer

Purpose

Despite numerous studies on the utility of GATA-3 as breast cancer marker, its comparison with other breast markers, its concordance between primary and metastatic tumors and its expression in primary cancers from sites with frequent breast metastases remains unclear.

Methods

To address these questions, totally 993 invasive breast cancers (IBC), 254 paired nodal metastases, 23 distant metastases, and 208 lung carcinomas were included. GATA-3 expression was analyzed by immunohistochemistry and compared to other breast markers [gross cystic disease fluid protein 15 (GCDFP-15) and mammaglobin (MGB)].

Results

GATA-3 was expressed in 82.5% of IBC, predominantly in luminal (93.9%), and lower in non-luminal cancers [59.6% of HER2 overexpressing (HER2-OE) and 38.1% of triple negative breast cancer (TNBC) subtypes]. GATA-3 identified more IBC than GCDFP-15 (23.9%) and MGB (46.6%). However, MGB showed a comparable sensitivity for non-luminal cancers to GATA-3. Combining MGB and GATA-3 improved sensitivity for both HER2-OE (80.8%) and TNBC cases (55.4%). GATA-3 showed a high sensitivity for nodal metastases and distant metastases, with good concordance with primary tumors. GATA-3 was expressed in 1.0% of lung carcinomas, with sensitivity and specificity of 82.5 and 99.0% in differentiating IBC and lung carcinoma.

Conclusions

GATA-3 expression was the highest in luminal breast carcinomas, and showed higher sensitivity than GCDFP-15 and MGB. However, in the poorly differentiated IBC, its utility was still limited. One should be aware of the possible GATA-3 expression in lung carcinomas.

     

乳腺浸润性导管癌免疫组化分层法的预后价值(英文)

Objective:Gene expression profiling of breast cancer has identified five molecularly distinct subtypes of breast cancer that have different biological behavior and clinical outcomes. These subtypes are termed luminal A, luminal B, luminal HER2, HER2-enriched and triple negative breast cancers (TNBC). We aimed at identification of breast cancer subtypes among Egyptian population and their clinicopathologic features using ER, PR and HER2, Ki-67 and CK5/6. Methods:Tumors from 100 patients with invasive duct carcinoma were subtyped by immunohistochemistry using ER, PR, HER2, Ki-67 and CK5/6. The prognostic value of the immunohistochemical assignment for breast cancer disease-specific survival was investigated by using Kaplan-Meier curves. Results:Immunohistochemical profiling classified 22 cases as luminal A, 33 cases as luminal B, 9 cases as luminal HER2, 26 cases as HER2-enriched and 10 cases as TNBC. Tumors that measured more than 3.5 cm, showed predominance of HER2-enriched subtype. HER2-enriched and luminal B subtypes dominated the node positive cases (35.4% and 33.8%; respectively). Large tumor size (> 3.5 cm), hormone receptor negative state and HER2 positive state were associated with poor prognosis. Disease free survivals (DFSs) were significantly different (P<0.0001) among different breast subtypes with worst 2-year DFS for HER2-enriched subtype (40.77%) followed by luminal A (63.56%). DFS was almost similar in the remaining other subtypes, and luminal B, luminal HER2 and TNBC which were 86.85%, 87.5% and 88.89%; respectively. Conclusion:ER, PR, HER2 and Ki-67 constituted a strong surrogate for molecular breast cancer subtypes and can be easily applied. HER2-enriched subtype carries worse features being associated with large tumor size, nodal metastasis and is associated with poor outcome. Luminal A is a heterogeneous subtype with underlying several factors that can turn its prognosis adversely. TNBC subtype may behave unexpected in a favorable way.     

Reproductive and hormonal risk factors for postmenopausal luminal, HER-2-overexpressing, and triple-negative breast cancer

BACKGROUND.

Molecular profiling studies have identified subtypes of breast cancer that can be approximately classified by estrogen receptor (ER), progesterone receptor (PR), and HER‐2/neu (HER‐2) expression. These molecular subtypes are prognostically significant, but to the authors' knowledge, differences in their etiologic profiles have not been established. Reproductive factors may plausibly be differentially correlated with the risk of different breast cancer subtypes because these factors are presumed to impact exposure to endogenous sex hormones.

METHODS.

The authors pooled 2 population‐based, case–control studies of breast cancer in women ages 55 to 79 years for an analysis including 1476 controls and 1023 cases of luminal breast cancer, 39 cases of HER‐2‐overexpressing breast cancer, and 78 cases of triple‐negative breast cancer. Polytomous logistic regression was used to compare each case group with controls.

RESULTS.

Associations varied by molecular subtype. Early age at menarche was only found to be associated with risk of HER‐2‐overexpressing disease (odds ratio [OR] of 2.7; 95% confidence interval [95% CI], 1.4‐5.5), whereas breastfeeding for ≥6 months was only found to be protective for luminal and triple‐negative disease (OR of 0.8 [95% CI, 0.6‐1.0] and OR of 0.5 [95% CI, 0.3‐0.9], respectively). Both late age at menopause and the use of estrogen plus progestin hormone therapy were only found to be associated with risk of luminal disease (OR of 1.6 [95% CI, 1.1‐2.2] and OR of 1.7 [95% CI, 1.3‐2.1], respectively). No differences in risks associated with parity or age at first live birth were observed by subtype.

CONCLUSIONS.

Certain reproductive factors may have a greater impact on the risk of certain molecular subtypes of disease compared with others. Future studies that further define the etiology of breast cancer subtypes will add to the biologic understanding of this disease. Cancer 2008. © 2008 American Cancer Society.     

Expression of aldehyde dehydrogenase 1 as a marker of mammary stem cells in benign and malignant breast lesions of Ghanaian women

BACKGROUND:

Breast cancers that are negative for the estrogen receptor (ER), the progesterone receptor (PR), and the HER2 (human epidermal growth factor receptor 2) marker are more prevalent among African women, and the biologically aggressive nature of these triple‐negative breast cancers (TNBCs) may be attributed to their mammary stem cell features. Little is known about expression of the mammary stem cell marker aldehyde dehydrogenase 1 (ALDH1) in African women. Novel data are reported regarding ALDH1 expression in benign and cancerous breast tissue of Ghanaian women.

METHODS:

Formalin‐fixed, paraffin‐embedded specimens were transported from the Komfo Anoyke Teaching Hospital in Kumasi, Ghana to the University of Michigan for centralized histopathology study. Expression of ER, PR, HER2, and ALDH1 was assessed by immunohistochemistry. ALDH1 staining was further characterized by its presence in stromal versus epithelial and/or tumor components of tissue.

RESULTS:

A total of 173 women contributed to this study: 69 with benign breast conditions, mean age 24 years, and 104 with breast cancer, mean age 49 years. The proportion of benign breast conditions expressing stromal ALDH1 (n = 40, 58%) was significantly higher than those with cancer (n = 44, 42.3%) (P = .043). Among the cancers, TNBC had the highest prevalence of ALDH1 expression, either in stroma or in epithelial cells. More than 2‐fold higher likelihood of ALDH1 expression was observed in TNBC cases compared with other breast cancer subtypes (odds ratio = 2.38, 95% confidence interval 1.03‐5.52, P = .042).

CONCLUSIONS:

ALDH1 expression was higher in stromal components of benign compared with cancerous lesions. Of the ER‐, PR‐, and HER2‐defined subtypes of breast cancer, expression of ALDH1 was highest in TNBC. Cancer 2013. © 2012 American Cancer Society.     

Reproductive history and the risk of molecular breast cancer subtypes in a prospective study of Norwegian women

Purpose

Breast cancer can be classified into molecular subtypes that differ in clinical characteristics and prognosis. There is some but conflicting evidence that reproductive risk factors may differ between distinct breast cancer subtypes.

Methods

We investigated associations of reproductive factors with the risk for six molecular breast cancer subtypes in a cohort of 21,532 Norwegian women who were born between 1886 and 1928 and followed up for breast cancer incidence between 1961 and 2008. We obtained stored tumor tissue from incident breast cancers and used immunohistochemistry and in situ hybridization to classify 825 invasive tumors into three luminal subtypes [Luminal A, Luminal B (HER2?) and Luminal B (HER2+)] and three non-luminal subtypes [human epidermal growth factor receptor 2 (HER2) subtype, basal-like phenotype (BP) and five negative phenotype (5NP)]. We used Cox regression to assess reproductive factors and risk for each subtype.

Results

We found that young age at menarche, old age at first birth and low parity were associated with increased risk for luminal breast cancer subtypes. For the HER2 subtype, we either found no association or associations in the opposite direction compared to the luminal subtypes. The BP subtype appeared to have a similar reproductive risk profile as the luminal subtypes. Breastfeeding was associated with a reduced risk for HER2 and 5NP subtypes, but was not associated with any other subtype.

Conclusions

The results suggest that molecular breast cancer subtypes differ in their reproductive risk factors, but associations with non-luminal subtypes are still poorly understood and warrant further study.     

Basal markers and prognosis in luminal breast cancer

Purpose

Basal marker expression in triple-negative breast cancers identifies basal-like tumours, and thus separates the TN group into two prognostic groups. However, the expression and prognostic significance of basal markers in luminal breast cancers are poorly described. The aim of this study was to investigate the expression and prognostic value of basal markers (CK5, CK14 and EGFR) in luminal breast cancer.

Methods

A total of 1423 formalin-fixed, paraffin-embedded breast cancer tumours from a well-characterized cohort of Norwegian women, previously reclassified into molecular subtypes using IHC and ISH, were included in the study. For the present study, tumours expressing at least one of the basal markers CK5, CK14 or EGFR were defined as basal marker positive. Cumulative incidence of death from breast cancer and hazard ratio analyses were used to assess prognosis according to basal marker expression.

Results and conclusion

In total, 470 cases (33.0%) were basal marker positive. A higher proportion of the basal marker-positive tumours were of histopathological grade 3 compared to basal marker negative. For hormone receptor-positive, HER2-negative cases, we found better prognosis for basal marker-positive breast cancer compared to basal marker negative. For all subtypes combined, poorer prognosis for basal marker-negative cases was found in histopathological grade 2 tumours but not among grade 1 and 3.

     

Differences in subtype distribution between screen-detected and symptomatic invasive breast cancer and their impact on survival

Purpose

Stage shift is considered a major reason for more favorable outcomes in patients with screen-detected breast cancer. However, even after adjusting for clinical stage, unresolved issues concerning the reasons for a survival benefit associated with screening programs remain. This study aims to evaluate differences in subtype distribution and outcomes among patients with screen-detected and symptomatic invasive breast cancer and assess whether variations in subtype distribution could explain differences in prognosis.

Methods

Survival analysis was performed to estimate the likelihood of distant recurrence and death in 1132 patients. Subtypes were defined as luminal A [estrogen receptor (ER)+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (HER2)?, and Ki67 low], luminal B (HER2?) (ER+ and/or PR+, HER2?, and Ki67 high), luminal B (HER2+) (ER+ and/or PR+ and HER2+), HER2 overexpressing (ER?, PR?, and HER2+), and triple negative (ER?, PR?, and HER2?).

Results

Screen-detected cancers had favorable clinicopathological characteristics, such as smaller tumor size and a lower frequency of lymph node involvement. Women with screen-detected cancers had a survival advantage. Subtype distribution differed significantly among women with screen-detected and symptomatic cancer. Screen-detected cancers were more likely to be luminal A and less likely to be HER2 overexpressing or triple negative cancer compared with symptomatic cancers (luminal A 61.3 vs. 44.2%, HER2 overexpressing 4.0 vs. 8.0%, triple negative 8.0 vs. 15.9%). Node status, mode of detection, and subtype were independent prognostic factors in the multivariate analysis.

Conclusions

Differences in subtype distribution between screen-detected and symptomatic cancer could partially explain differences in outcomes.

     

Breast cancer subtypes and response to systemic treatment after whole‐brain radiotherapy in patients with brain metastases

BACKGROUND:

The aim of this study was to assess the role of systemic treatment after whole‐brain radiotherapy (WBRT) in immunohistochemically defined biological subsets of breast cancer patients with brain metastases.

METHODS:

The group of 420 consecutive breast cancer patients with brain metastases treated at the same institution between the years of 2003 to 2009 was analyzed. Patients were divided into 4 immunohistochemically biological subsets, based on the levels of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) receptors, and labeled as luminal A, luminal B, HER2, and triple‐negative. Survival from brain metastases with and without systemic treatment after WBRT was calculated in 4 subsets.

RESULTS:

In the entire group, the median survival from brain metastases in patients without and with systemic treatment after WBRT was 3 and 10 months, respectively (P < .0001). In the triple‐negative subset, the median survival from brain metastases with and without systemic treatment was 4 and 3 months (P = .16), and in the luminal A subset, it was 12 and 3 months, respectively (P = .003). In the luminal B subset, the median survival without further treatment, after chemotherapy and/or hormonal therapy, and after chemotherapy and/or hormonal therapy with targeted therapy was 2 months, 9 months, and 15 months, respectively (P < .0001). In the HER2 subset, the median survival was 4 months, 6 months, and 13 months, respectively (P < .0001). No significant response to systemic treatment was noted in the triple‐negative breast cancer population.

CONCLUSIONS:

Systemic therapy, ordered after WBRT, appears to improve survival in patients with the luminal A, luminal B, and HER2 breast cancer subtypes. Targeted therapy was found to have an additional positive impact on survival. In patients with triple‐negative breast cancer, the role of systemic treatment after WBRT appears to be less clear, and therefore this issue requires further investigation. Cancer 2010. © 2010 American Cancer Society.     

Association between mammographic density and basal-like and luminal A breast cancer subtypes

Introduction

Mammographic density is a strong risk factor for breast cancer overall, but few studies have examined the association between mammographic density and specific subtypes of breast cancer, especially aggressive basal-like breast cancers. Because basal-like breast cancers are less frequently screen-detected, it is important to understand how mammographic density relates to risk of basal-like breast cancer.

Methods

We estimated associations between mammographic density and breast cancer risk according to breast cancer subtype. Cases and controls were participants in the Carolina Breast Cancer Study (CBCS) who also had mammograms recorded in the Carolina Mammography Registry (CMR). A total of 491 cases had mammograms within five years prior to and one year after diagnosis and 528 controls had screening or diagnostic mammograms close to the dates of selection into CBCS. Mammographic density was reported to the CMR using Breast Imaging Reporting and Data System categories. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 1 and 2 (HER1 and HER2), and cytokeratin 5/6 (CK5/6) were assessed by immunohistochemistry and dichotomized as positive or negative, with ER+ and/or PR+, and HER2- tumors classified as luminal A and ER-, PR-, HER2-, HER1+ and/or CK5/6+ tumors classified as basal-like breast cancer. Triple negative tumors were defined as negative for ER, PR and HER2. Of the 491 cases 175 were missing information on subtypes; the remaining cases included 181 luminal A, 17 luminal B, 48 basal-like, 29 ER-/PR-/HER2+, and 41 unclassified subtypes. Odds ratios comparing each subtype to all controls and case-case odds ratios comparing mammographic density distributions in basal-like to luminal A breast cancers were estimated using logistic regression.

Results

Mammographic density was associated with increased risk of both luminal A and basal-like breast cancers, although estimates were imprecise. The magnitude of the odds ratio associated with mammographic density was not substantially different between basal-like and luminal A cancers in case–control analyses and case-case analyses (case-case OR = 1.08 (95% confidence interval: 0.30, 3.84)).

Conclusions

These results suggest that risk estimates associated with mammographic density are not distinct for separate breast cancer subtypes (basal-like/triple negative vs. luminal A breast cancers). Studies with a larger number of basal-like breast cancers are needed to confirm our findings.     

Differences in Clinical Outcomes between Luminal A and B Type Breast Cancers according to the St. Gallen Consensus 2013

Purpose

Human epidermal growth factor receptor 2 (HER2)-positive luminal B type comprises estrogen receptor (ER)-positive and HER2-positive cancers, and HER2-negative luminal B type comprises ER-positive cancers showing a Ki-67 labeling index ≥14% or progesterone receptor (PR) expression of <20% according to the St. Gallen consensus 2013. The current study aimed to classify intrinsic subtypes according to the St. Gallen consensus 2013 and determine the differences in clinicopathological parameters and survival outcomes among the molecular types, especially among the luminal types.

Methods

Assessment of molecular types was performed for 267 invasive ductal carcinomas. The differences in clinicopathological parameters, disease-free survival (DFS), and overall survival (OS) among the molecular types were analyzed.

Results

The luminal B type was the most prevalent, at 44.9%, followed by the luminal A, triple-negative (including basal-like type), and HER2 type, at 21.7%, 18.7%, and 14.6%, respectively. There were statistically significant differences in size (p=0.003), nodal status (p=0.046), histologic grade (p<0.001), p53 (p<0.001) and cyclooxygenase 2 (COX-2) positivity (p=0.002), recurrence (p=0.001) and death rates (p=0.036), DFS (p=0.002), and OS (p=0.039) among the molecular types. Significant differences in size (p=0.009), nodal metastasis (p=0.019), histologic grade (p<0.001), p53 positivity (p=0.001), and PR expression (p<0.001) were noted between the luminal A and B types. Among the luminal B type cancers, the distributions of ER and PR scores showed significant differences (p=0.003, p=0.003). p53 positivity in the luminal B type cancers was related to shortened DFS (p=0.034). In luminal type cancers, COX-2 positivity was related to longer DFS (p=0.026).

Conclusion

Different management guidelines should be considered for the luminal A and luminal B breast cancer types. Positive p53 expression in luminal B type cancers and negative COX-2 expression in luminal type cancers seem to be related to poor clinical outcome.     

Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer

Prior studies have suggested a higher prevalence of high grade, ER-negative, HER2-positive, and basal-like carcinomas in young women with breast cancer. However, the precise distribution of poor prognostic features in this population remains unclear. We examined the pathologic features and distribution of molecular phenotype in relation to patient age in a large group of young women (≤40?years) with invasive breast cancer. Medical records were reviewed for clinical characteristics, tumor stage, and receptor status. Pathologic features, including those features associated with basal-like carcinomas, were examined by central review. Using tumor grade and biomarker expression, cancers were categorized as luminal A (ER+ and/or PR+ and HER2-, histologic grade 1 or 2); luminal B (ER+ and/or PR+ and HER2+, or ER and/or PR+, HER2- and grade 3); HER2 (ER and PR- and HER2+); and triple negative (ER-, PR-, and HER2-). Among 399 women?of ≤40?years, 33% had luminal A tumors, 35% luminal B, 11% HER2 (ER-negative), and 21% triple negative. Compared to published results for all breast cancers, a greater proportion of young women had luminal B tumors, and a lesser proportion had luminal A. There were no significant differences in molecular phenotype, tumor stage or grade among the different age groups of young women. However, this population of young women presented with a different distribution of molecular phenotypes compared to the general population of women with breast cancer. These findings may have implications with regard to the etiology and prognosis of breast cancer in young women.     

Analysis of terminal duct lobular unit involution in luminal A and basal breast cancers

Introduction

Involution of terminal duct lobular units (TDLUs), the structures that give rise to most breast cancers, has been associated with reduced breast cancer risk. Data suggest that the etiology and pathogenesis of luminal A and core basal phenotype (CBP) breast cancers differ, but associations with TDLU involution are unknown. Accordingly, we performed a masked microscopic assessment of TDLU involution in benign tissues associated with luminal A and CBP breast cancers diagnosed among women less than age 55 years.

Methods

Cases were participants in a population-based case-control study conducted in Poland. Increased TDLU involution was defined as fewer acini per TDLU or shorter TDLU diameter. Luminal A was defined as estrogen receptor (ER) positive and/or progesterone receptor (PR) positive and human epidermal growth factor receptor 2 (HER2) negative and CBP as negative for ER, PR, and HER2 with expression of basal cytokeratins or epidermal growth factor receptor (EGFR). We performed logistic regression to evaluate associations between TDLU involution and tumor subtypes, adjusted for clinical characteristics and breast cancer risk factors.

Results

Among 232 luminal A and 49 CBP cancers associated with evaluable TDLUs, CBP tumors were associated with significantly greater average number of acini per TDLU (odds ratio (OR) = 3.36, 95% confidence interval (CI) = 1.36 to 8.32, P = 0.009) and larger average TDLU diameter (OR = 2.49, 95% CI = 1.08 to 5.74, P = 0.03; comparing highest to lowest group, adjusted for age and study site).

Conclusions

We suggest that TDLU involution is less marked in benign tissues surrounding CBP as compared to luminal A cancers, which may reflect differences in the etiology and pathogenesis of these tumor subtypes.