Monica Jernberg Engstrøm

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

PurposeBreast 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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.

Invasive lobular breast cancer: the prognostic impact of histopathological grade, E-cadherin and molecular subtypes

The aim of this study was to compare breast cancer specific survival (BCSS) for invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) and, further, to evaluate critically the prognostic value of histopathological grading of ILC and examine E‐cadherin as a prognostic marker in ILC.

Alterations in collagen fibre patterns in breast cancer. A premise for tumour invasiveness

Stromal tissue in the breast plays a key role in cancer invasiveness due to molecular and cellular changes. Collagen is the main component of the stroma. The purposes of this study were to investigate differences in collagen fibre patterns between tumour‐induced stromal tissue and normal stroma, and between high‐grade and low‐grade breast cancer stroma, using second harmonic generation microscopy. Thirty‐seven ductal carcinomas were examined: Twenty‐one Luminal A phenotype and sixteen HER2 or Basal‐like phenotype. Three regions were examined in each case: intratumoral, juxtatumoral and extratumoral. Two images were captured in each region. Two characteristics of collagen fibres were examined: the degree of straightness, and the degree of alignment. Collagen fibres were visually classified as curly, intermediate or straight, and as parallel or not parallel. The results of angle measurement and visual analysis showed that collagen fibres were straightest in the intratumoral region and curliest in the extratumoral region. Collagen fibres were more parallel in the juxtatumoral region compared to the two other regions. There were no significant differences between high‐grade and low‐grade tumours. As a breast tumour progresses, collagen fibres appear to straighten and align at the tumour boundary. This could facilitate invasion of the tumour into the surrounding stroma.

TOP2A gene copy number change in breast cancer.

Aims The clinical significance of TOP2A as a prognostic marker has not been clarified. The aims of this study were to investigate the frequency of TOP2A copy number change; to correlate TOP2A with HER2 status, hormone receptor (HR) status and molecular subtype, and further to explore differences in breast cancer-specific survival according to TOP2A and HER2. Methods In this study, TOP2A, HER2 and chromosome 17 copy number were assessed in 670 cases of breast cancer using in situ hybridisation techniques. Gene to chromosome ratios ≥2 were classified as amplification. TOP2A deletion (gene to chromosome ratio ≤0.8) or monosomy (only one signal for both gene and chromosome in more than 75% of nuclei) were classified as gene loss. Results A strong association between TOP2A change and HR and HER2 status was found. During the first 5 years after diagnosis, the risk of death from breast cancer was significantly higher for cases with HER2 amplification irrespective of TOP2A status. Conclusions TOP2A copy number change was strongly associated with HR and HER2 status and as a prognostic marker TOP2A is probably of limited value.

Molecular Subtypes of Breast Cancer: Long-term Incidence Trends and Prognostic Differences

Background: Secular trends in incidence and prognosis of molecular breast cancer subtypes are poorly described. We studied long-term trends in a population of Norwegian women born 1886–1977. Methods: A total of 52,949 women were followed for breast cancer incidence, and 1,423 tumors were reclassified into molecular subtypes using IHC and in situ hybridization. We compared incidence rates among women born 1886–1928 and 1929–1977, estimated age-specific incidence rate ratios (IRR), and performed multiple imputations to account for unknown subtype. Prognosis was compared for women diagnosed before 1995 and in 1995 or later, estimating cumulative risk of death and HRs. Results: Between 50 and 69 years of age, incidence rates of Luminal A and Luminal B (HER2−) were higher among women born in 1929 or later, compared with before 1929 [IRRs 50–54 years; after imputations: 3.5; 95% confidence interval (CI), 1.8–6.9 and 2.5; 95% CI, 1.2–5.2, respectively], with no clear differences for other subtypes. Rates of death were lower in women diagnosed in 1995 or later, compared to before 1995, for Luminal A (HR 0.4; 95% CI, 0.3–0.5), Luminal B (HER2−; HR 0.5; 95% CI, 0.3–0.7), and Basal phenotype (HR 0.4; 95% CI, 0.2–0.9). Conclusions: We found a strong secular incidence increase restricted to Luminal A and Luminal B (HER2−) subtypes, combined with a markedly improved prognosis for these subtypes and for the Basal phenotype. Impact: This study documents a clear secular increase in incidence and a concomitant improved prognosis for specific molecular breast cancer subtypes. Cancer Epidemiol Biomarkers Prev; 25(12); 1625–34. ©2016 AACR.

Anthropometric factors and risk of molecular breast cancer subtypes among postmenopausal Norwegian women

Adult height and body weight are positively associated with breast cancer risk after menopause, but few studies have investigated these factors according to molecular breast cancer subtype. A total of 18,562 postmenopausal Norwegian women who were born between 1886 and 1928 were followed up for breast cancer incidence from the time (between 1963 and 1975) height and weight were measured until 2008. Immunohistochemical and in situ hybridization techniques were used to subtype 734 incident breast cancer cases into Luminal A, Luminal B [human epidermal growth factor receptor 2 (HER2−)], Luminal B (HER2+), HER2 subtype, basal‐like phenotype (BP) and five‐negative phenotype (5NP). We used Cox regression analysis to assess adult height and body mass index (BMI) in relation to risk of these subtypes. We found a positive association of height with risk of Luminal A breast cancer (ptrend, 0.004), but there was no clear association of height with any other subtype. BMI was positively associated with risk of all luminal breast cancer subtypes, including Luminal A (ptrend, 0.002), Luminal B (HER2−) (ptrend, 0.02), Luminal B (HER2+) (ptrend, 0.06), and also for the HER2 subtype (ptrend, 0.04), but BMI was not associated with risk of the BP or 5NP subtypes. Nonetheless, statistical tests for heterogeneity did not provide evidence that associations of height and BMI differed across breast cancer subtypes. This study of breast cancer risk among postmenopausal women suggests that height is positively associated with risk of Luminal A breast cancer. BMI is positively associated with risk of all luminal subtypes and for the HER2 subtype.

HER2 gene copy number and breast cancer specific survival

HER2 amplification occurs in 10–15% of breast cancers. It is associated with poor breast cancer‐specific survival (BCSS) and is an important prognostic and predictive marker. While it has been accepted that the HER2:chromosome 17 centromere (CEP17) ratio determines HER2 status, recent guidelines acknowledge the significance of HER2 copy number alone. The aims of this study were to assess BCSS according to mean HER2 copy number and HER2 status expressed as a HER2:CEP17 ratio with and without increased CEP17 copy number.

Characterization of FGD5 Expression in Primary Breast Cancers and Lymph Node Metastases

Faciogenital dysplasia 5 (FGD5) amplification drives tumor cell proliferation, and is present in 9.5% of breast cancers. We describe FGD5 expression, assess associations between FGD5 amplification and FGD5 expression, and assess FGD5 expression in relation to proliferation and prognosis. FGD5 immunohistochemistry was done on primary tumors (n=829) and lymph node metastases (n=231) from a cohort of Norwegian patients. We explored associations between FGD5 amplification, FGD5 expression, and proliferation, and analyzed the prognostic value of FGD5 expression by estimating cumulative risks of death and hazard ratios (HRs). We identified nuclear and cytoplasmic expression in 64% and 73% of primary tumors, respectively, and found an association between gene amplification and nuclear expression (p=0.02). The proportion of cases with FGD5 expression was higher in lymph node metastases, compared with primary tumors (p=0.004 for nuclear and p=0.001 for cytoplasmic staining). Neither proliferation nor prognosis was associated with FGD5 expression (age-adjusted HR 1.12 [95% confidence interval = 0.89–1.41] for nuclear expression; and 0.88 [95% CI = 0.70–1.12] for cytoplasmic expression). FGD5 is expressed in a high proportion of breast cancers and lymph node metastases. There was a correlation between FGD5 amplification and nuclear expression, but no association between FGD5 expression and proliferation or prognosis.

The prognostic value of androgen receptors in breast cancer subtypes

PurposeAndrogen receptor (AR) expression is frequent in breast cancer and has been associated with good prognosis in several studies. The present study investigates AR-expression in relation to molecular subtypes, clinicopathological features and prognosis in 1297 primary tumours and 336 paired axillary lymph node metastases (LNM) from two cohorts of Norwegian patients.MethodsImmunohistochemistry for AR was performed on tumours previously reclassified into molecular subtypes using immunohistochemistry and in situ hybridisation. Associations between AR-expression and clinical features were studied using Chi-square tests. Cumulative incidence of breast cancer death and Cox regression analyses were used to assess prognosis.ResultsAR-positivity was found in 78.0% of all cases, 84.9% of luminal and 45.1% of non-luminal tumours. The highest proportion of AR-positivity was found in Luminal B tumours, and the lowest in the Basal phenotype. Discordance in AR-status between primary tumours and lymph node metastases was observed in 21.4% of cases. A switch from AR− primary tumour to AR+ lymph node metastasis was seen in 60/72 discrepant cases. AR-expression in primary tumours was an independent and favourable prognostic marker (HR 0.70, 95% CI 0.55–0.90), particularly in the Luminal A subtype, and in grade 3 tumours.ConclusionsAR is an independent predictor of good prognosis in BC, particularly in grade 3 and Luminal A tumours. Discordant AR-expression between primary tumour and LNM was observed in 21.4% of cases and most often there was a switch from AR− primary tumour to AR+ axillary LNM.

Basal markers and prognosis in luminal breast cancer

PurposeBasal 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.MethodsA 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 conclusionIn 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.