Longer Breast Cancer-specific Survival Research Articles

Higher-risk breast cancer in women aged 80 and older: Exploring the effect of treatment on survival

BackgroundTo understand the association between various treatments and survival for older women with higher-risk breast cancer when controlling for patient and tumor factors. Materials and methodsWe conducted a retrospective, population-based study. Women aged 80 years or older and diagnosed between 2004 and 2017 with non-metastatic, higher-risk breast cancer were identified form the provincial cancer registry in Alberta, Canada. Higher-risk was defined as any of following: T3/4, node positive, human epidermal factor receptor-2 (Her2) positive or triple negative disease. Treatments were surgery, radiotherapy and systemic therapy (hormonal therapy, and/or chemotherapy and/or trastuzumab) or a combination of the previous. Cox regression models were used to examine the association between treatments and breast cancer specific survival (BCSS) and overall survival (OS). Results1369 patients were included. The median age was 84 years. 332 (24%) of women had T3-T4 tumors, 792 (58%) had nodal involvement, 130 (10%) had Her2 positive tumors, 124 (9%) had triple negative tumors. After a median follow-up of 35 months, 29.5% of patients died of breast cancer whereas 34.2% died from other causes. Patients had a lower adjusted hazard for BCSS if they had surgery (hazard ratio [HR] = 0.37 95% confidence interval [CI]: 0.27, 0.51), or systemic therapy (HR = 0.75, 95%CI: 0.58, 0.98). Patients had an increased probability of breast cancer death in the first 5 years after diagnosis compared to death from other causes. ConclusionsSurgery and systemic therapy were associated with longer BCSS and OS. This suggests that maximizing treatments might benefit higher-risk patients.

The prognostic significance of BMI1 expression in invasive breast cancer is dependent on its molecular subtypes

PurposeBMI1, which is a major component of the polycomb group complex 1, is an essential epigenetic repressor of multiple regulatory genes and has been identified as a cancer stem cell (CSC) marker in several cancers. However, its role in breast cancer (BC) remains to be defined. In this study, we have evaluated the prognostic significance of BMI1 among the different molecular subtypes and assessed its association with other breast CSC markers (BCSC).Material and methodBMI1 copy number and mRNA was assessed in large and well-characterised cohorts of early-stage BC patients [METABRIC (n = 1980) and the Bc-GenExMiner (n = 9616) databases]. BMI1 protein expression was assessed using tissue microarray and immunohistochemistry in a cohort of 870 invasive BC patients with long-term outcome data and the expression of a panel of BCSC markers was monitored.ResultBMI1 expression, prognostic significance and its association with BCSC markers were differed between molecular classes. In the luminal oestrogen receptor-positive (ER+) BC, BMI1 showed significantly higher expression compared to ER− tumours. BMI1 showed positive correlation with favourable prognostic features and it was negatively associated with the expression of key BCSC markers (ALDH1A1, CD24, CD44, CD133, SOX10 and SOX9). High expression of BMI1 was associated with longer breast cancer-specific survival (BCSS) independent of other prognostic variables. In the basal triple negative BC subtype, BMI1 expression showed positive association with CD133 and SOX10 and it was significantly associated with shorter BCSS.ConclusionHigh BMI1 expression is associated with clinicopathological variables and outcome in BC. However, this association is dependent on the molecular subtypes. Further functional assessment to detect its underlying mechanistic roles in BC subtypes is warranted.

The solute carrier SLC7A8 is a marker of favourable prognosis in ER-positive low proliferative invasive breast cancer

PurposeBreast cancer (BC) is a heterogeneous disease consisting of various subtypes, with different prognostic and therapeutic outcomes. The amino acid transporter, SLC7A8, is overexpressed in oestrogen receptor-positive BC. However, the consequence of this overexpression, in terms of disease prognosis, is still obscure. This study aimed to evaluate the biological and prognostic value of SLC7A8 in BC with emphasis on the intrinsic molecular subtypes.MethodsSLC7A8 was assessed at the genomic, using METABRIC data (n = 1980), and proteomic, using immunohistochemistry and TMA (n = 1562), levels in well-characterised primary BC cohorts. SLC7A8 expression was examined with clinicopathological parameters, molecular subtypes, and patient outcome.ResultsSLC7A8 mRNA and SLC7A8 protein expression were strongly associated with good prognostic features, including small tumour size, low tumour grade, and good Nottingham Prognostic Index (NPI) (all P < 0.05). Expression of SLC7A8 mRNA was higher in luminal tumours compared to other subtypes (P < 0.001). High expression of SLC7A8 mRNA and SLC7A8 protein was associated with good patient outcome (P ≤ 0.001) but only in the low proliferative ER+/luminal A tumours (P = 0.01). In multivariate analysis, SLC7A8 mRNA and SLC7A8 protein were independent factors for longer breast cancer specific survival (P = 0.01 and P = 0.03), respectively.ConclusionSLC7A8 appears to play a role in BC and is a marker for favourable prognosis in the most predominant, ER+ low proliferative/luminal A, BC subtype. Functional assessment is necessary to reveal the specific role played by SLC7A8 in ER+ BC.

Prognostic significance of KN motif and ankyrin repeat domains 1 (KANK1) in invasive breast cancer

BackgroundKN motif and ankyrin repeat domains 1 (KANK1) plays an important role in cytoskeleton maintenance and contributes to the regulation of cell proliferation, adhesion and apoptosis. KANK1 is involved in progression of a variety of solid tumours; however, its role in invasive breast cancer (BC) remains unknown. This study aims to evaluate the clinicopathological and prognostic value of KANK1 expression in operable BC.MethodsKANK1 expression was assessed at the transcriptomic level using multiple BC cohorts; the Molecular Taxonomy of BC International Consortium cohort (METABRIC; n = 1980), The Cancer Genome Atlas BC cohort (TCGA; n = 949) and the publicly available BC transcriptomic data hosted by BC Gene-Expression Miner (bc-GenExMiner v4.0) and Kaplan–Meier plotter?. The Nottingham BC cohort (n = 1500) prepared as tissue microarrays was used to assess KANK1 protein expression using immunohistochemistry (IHC). The association between clinicopathological variables and patient outcome was investigated.ResultsIn the METABRIC cohort, high expression of KANK1 mRNA was associated with characteristics of good prognosis including lower grade, absence of lymphovascular invasion and HER2 negativity (all; p < 0.001) and with better outcome [p = 0.006, Hazards ratio, (HR) 0.70, 95% CI 0.54–0.91]. High KANK1 protein expression was correlated with smaller tumour size and HER2 negativity, and better outcome in terms of longer breast cancer-specific survival [p = 0.013, HR 0.7, 95% CI 0.536–0.893] and time to distant metastasis [p = 0.033, HR 0.65, 95% CI 0.51–0.819].ConclusionThese results supported that upregulation of KANK1 works as a tumour suppressor gene in BC and is associated with improved patients’ outcomes.

Effect of glucocorticoid use on survival in patients with stage I-III breast cancer.

Glucocorticoids (GCs) are commonly used in breast cancer patients to ameliorate emesis induced by chemotherapy. Some preclinical studies have suggested that systemic GCs might promote survival of estrogen receptor (ER)-negative breast cancer cells. This study aims to clarify their clinical effect on patient survival. A total of 18,596 women with newly diagnosed stage I-III breast cancer in 2002-2006 were identified from the Taiwan Cancer Database and drug treatment was examined from the Taiwan National Health Insurance Claims Database. Of these, 3989 who did not receive adjuvant chemotherapy (non-chemotherapy cohort) and 3237 patients who received six cycles of adjuvant anthracycline-based chemotherapy (anthracycline cohort) were included. The impact of GC use on survival was analyzed separately in these two cohorts using Cox proportional hazards models. In the non-chemotherapy cohort, GC use was associated with aggressive clinicopathological features of breast cancer. High-dose GC was associated with shorter overall survival in univariate analysis but not in multivariate analysis. In the anthracycline cohort, multivariate analysis showed that GC use at each dose level was significantly associated with longer breast cancer-specific survival (HR 0.65, 0.70, and 0.70 for low-dose, median-dose, and high-dose GC, respectively) and overall survival (HR 0.72, 0.76, and 0.73, respectively) when compared with those receiving no GC. The associations were significant in both ER-positive and ER-negative subgroups for breast cancer-specific survival, and in ER-negative subgroup for overall survival. Concomitant use of GC improved survival in patients receiving adjuvant anthracycline-based chemotherapy for stage I-III breast cancer.

Low levels of intra-tumoural T cells in breast cancer identify clinically frail patients with shorter disease-specific survival.

The global health status of older patients with cancer influences their clinical course, but little is known regarding the influence of the immune system on the global health of older patients with cancer. The goal of this study was to assess the relationships between patient fitness/frailty status and survival, and the local tumour immune environment of older patients with breast cancer. In a cohort of 58 older patients with breast cancer (over 70 years of age), fluorescence microscopy was used to investigate whether levels of intra-tumoural T cells (CD3+) and granulocytic cells (CD15+) could predict clinical outcome, and/or whether they correlated with patient physical and mental performance as evaluated by comprehensive geriatric assessment. We observed that patients with higher levels of intra-tumoural T cells were fitter according to a number of clinical health measures including G8 (p = 0.006), Karnofsky Index (p = 0.0372), and Leuven Oncology Frailty Score (LOFS) (p = 0.0187). In contrast, high relative levels of granulocytic cells were found in patients with poorer clinical health (LOFS, p = 0.0474). Furthermore, high levels of T cells but not granulocytic cells were associated with longer breast cancer-specific survival (p = 0.0444). This is the first study to show that low relative levels of intra-tumoural T cells are associated with inferior patient fitness. In contrast to T cells, we observed that intra-tumoural granulocytic cells displayed an inverse relationship with patient performance. Further research is needed to determine whether boosting the level of intra-tumoural T cells in older non-fit patients can result in improved outcome.

275P - First-line treatment patterns by age for patients (pts) with HER2+ metastatic breast cancer (MBC) in the SystHERs registry

Background: Clinical outcomes for pts with HER2+ MBC may differ by age, potentially influenced by differences in treatment regimens administered to older vs younger pts. Systematic Therapies for HER2+ Metastatic Breast Cancer Study (SystHERs) captures real-world treatment patterns and outcomes in pts with HER2+ MBC. Here, we examine baseline characteristics, first-line treatments, and breast cancer–specific survival (BCSS) by age. Methods: SystHERs is a fully enrolled (Jun 2012–Jun 2016), ongoing, US-based, observational study. Pts were ≥18 years old and had HER2+ MBC diagnosed within 6 months of enrollment. Pts were grouped by age at MBC diagnosis (<50, 50–69, or ≥ 70 years) and compared descriptively. BCSS was defined as time from the date of MBC diagnosis to date of death due to MBC progression. Results: As of Feb 10, 2017, of 978 eligible pts, 287 were <50 years old, 563 were 50–69, and 128 were ≥70 at MBC diagnosis. Median follow-up from MBC diagnosis was 23, 22, and 19 months, respectively. Baseline characteristics, first-line treatments, and BCSS are shown (Table). In pts who received chemotherapy, docetaxel was the most common agent in pts <50 (67%) and 50–69 (64%) followed by paclitaxel (29% in both groups), whereas in pts ≥70, 43% and 45% received docetaxel and paclitaxel, respectively.Table275P<50 years (n = 287)50-69 years (n = 563)≥70 years (n = 128)Baseline characteristicsMedian age at MBC diagnosis, years (range)43 (21–49)59 (50–69)75 (70–90)Eastern Cooperative Oncology Group performance score 0–1, n (%)249 (87)476 (85)101 (79)De novo, n (%)158 (55)278 (49)52 (41)Median time from early breast cancer diagnosis to MBC diagnosisaIn pts with recurrent MBC only. H, trastuzumab; P, pertuzumab., months (range)36 (9–166)50 (5–329)42 (4–452)Estrogen receptor positive and/or progesterone receptor positive, n (%)203 (71)387 (69)96 (75)Visceral disease, n (%)196 (68)378 (67)75 (59)≥3 metastatic sites, n (%)87 (30)183 (33)32 (25)Bone metastasis, n (%)165 (57)282 (50)57 (45)Liver metastasis, n (%)117 (41)216 (38)33 (26)First-line treatments, n (%) (Treatments are not mutually exclusive)Any HER2-targeted therapy PH H without P275 (96) 229 (80) 37 (13)531 (94) 414 (74) 93 (17)116 (91) 68 (53) 44 (34)Any chemotherapy PH + taxane H without P + taxane254 (89) 207 (72) 18 (6)489 (87) 386 (69) 53 (9)86 (67) 55 (43) 16 (13)Any hormonal therapy With PH With H without P113 (39) 91 (32) 18 (6)230 (41) 161 (29) 48 (9)67 (52) 30 (23) 28 (22)Breast cancer -specific survival, % (95% confidence interval)Breast cancer–specific survival rate 12 months 24 months 36 months95 (92–97) 86 (81–90) 78 (71–84)92 (89–94) 80 (76–84) 68 (63–73)92 (85–95) 80 (71–87) 64 (48–76)a In pts with recurrent MBC only. H, trastuzumab; P, pertuzumab. Open table in a new tab Conclusions: In this preliminary real-world analysis of pts with HER2+ MBC, pertuzumab (P) + trastuzumab (H) was more commonly used than H without P across all age groups. Pts <50 and 50–69 years old more commonly received PH + taxane than those ≥70 (72% and 69% vs 43%, respectively). Compared with younger pts, those ≥70 received regimens with chemotherapy less commonly (89% and 87% vs 67%), and more commonly received regimens with H without P (13% and 17% vs 34%) or hormonal therapy (39% and 41% vs 52%). Pts <50 had longer BCSS than those ≥70 (78% vs 64% at 3 years). Clinical trial identification: NCT01615068 Legal entity responsible for the study: Genentech/Roche Funding: Genentech/Roche Disclosure: M. Jahanzeb: Consulting fees from Roche. Data and Safety Monitoring Board for Puma. D. Tripathy: Consulting fees from Puma Biotech, NEKTAR Pharma, Novartis. Contracted research paid to institution from Novartis. S.A. Hurvitz: Research funding from Amgen, Bayer, Boehringer Ingleheim, Genentech, GSK, Pfizer, Roche, Biomarin, Merrimack, PUMA, Dignitana, Medication. Research and travel from Lilly, Novartis, OBI Pharma. J. O'Shaughnessy: Consulting fees from Genentech. G. Mason: Advisory Board: Avon Foundation for Women Scientific. D.A. Yardley: Fees for services from Novartis and Genentech. Contracted research paid to institution from Genentech and Novartis. A. Brufsky: Consulting fees from Roche. H.S. Rugo: Fees for services from Genomic Health. contracted research paid to institution from Genentech, Pfizer, Novartis, Lilly, OBI Pharma, GTX, Macrogenics, Merck. M. Cobleigh: Royalties and Receipt of IP rights from Genomic Health. Consulting fees from Genentech/Roche and GSK. Contracted research from Genentech/Roche, Merrimack, Macrogenics, NRG foundation. S.M. Swain: Consulting fees from Genentech/Roche, Novartis, and Pieris. Contracted research paid to institution from Genentech/Roche, Pfizer, Merrimack, and Lilly. L. Chu, V. Antao, B. Yoo: Employment at Genentech. Stock ownership in Roche. P.A. Kaufman: Consulting fees from Genentech. Contracted research paid to institution from Genentech/Roche.

Guideline adherence and clinical outcome in vulnerable and healthy breast cancer patients: Results of a prospective cross-sectional study in Germany.

e18132 Background: In 2003 the German Cancer Society and the German Society for Breast Disease introduced a number of Quality Indicators (QIs) to improve standards of breast cancer care. Although QIs should be based on clinical evidence, evidence for important subpopulations (i.e. vulnerable patients) is often limited. In this prospective cross-sectional study we assessed conformity and non-conformity of guidelines and their impact on clinical outcome in a real-world setting. Methods: This prospective analysis included patients with primary breast cancer. Patients with stage IV and recurrent breast cancer were excluded. Data was collected from 2012-2016 in six certified breast care centers using a personal questionnaire and data from the patients' medical records. Guideline adherence to a set of 11 QIs was explored. Overall survival (OS) and disease free survival (DFS) were correlated with fulfillment of QIs and tumor characteristics. Results: Survival analysis was conducted in 2390 patients with a median follow-up of 16 months. 88 (4%) patients had a recurrent disease. 31 (1.3%) patients died of breast cancer. Tumor stage, grading, Her2- and hormone receptor status and Ki-67 correlated with DFS and OS. 1725/1907 patients (90.5%) received a guideline adherent treatment. The most prevalent reasons for non-conformity were old age (24.7%) and/or comorbidity (20.9%). Breast cancer specific DFS and OS were not significantly different between patients treated adherent or not adherent to the guidelines. In contrast, survival analysis of death other than breast cancer showed a significantly worse OS (p = 0.006) for patients not treated according to guideline recommendation. Conclusions: Conformity of clinical guidelines was observed in the majority of patients including healthy and vulnerable patients. These patients tended to have a longer breast cancer specific survival. Patients who were not considered suitable for guideline-adherent therapy died more often from other medical reasons rather than from breast cancer. In our study 10% of the patients had a limited life expectancy due to old age and co-morbidities with no assumed benefit from guideline adherence.

Abstract P1-04-04: KSR1 is involved in functional interaction between p53 and BRCA1 and is an independent predictor of overall survival in breast cancer

Abstract Background: Our recent human kinome screening to identify new regulators of estrogen receptor α (ERα) suggested an important role of kinase suppressor of ras 1 (KSR1) in breast cancer. KSR1 was originally identified as a positive regulator interacting with both RAS and RAF in the mitogen-activated protein kinase (MAPK) pathway. Recent studies have suggested that KSR1 may have dual functions as a scaffolding protein and also a protein kinase. Although KSR1 has been implicated in Ras-dependent cancers, its clinical significance and function in breast cancer have not been elucidated. Methods: The clinical significance of KSR1 was assessed by analyzing its expression in breast cancer tissue microarrays (TMAs, n=1000) by immunohistochemistry. Pearson chi2 and Fisher's Exact Test were used to correlate the expression levels with various tumor biomarkers; Kaplan Meier analyses were used to investigate impact on disease-free (DFS) and overall survival (OS). Multivariate Cox-proportional hazards analysis was also performed to evaluate the significant of KSR1 as an independent factor in breast cancer-specific survival (BCSS) and disease-free interval (DFI). The expression levels of KSR1 in breast cancer cell lines were measured by RT-qPCR and western blotting. A KSR1 stable over-expression breast cancer cell line (MCF7-KSR1) was generated to study its effect on growth and colony formation by 3D matrigel assay and soft agar assay in vitro. Furthermore, MCF7-KSR1 stable cells were also used in nude mice xenograft model in vivo. Luciferase reporter assay was employed to examine the effect of KSR1 on p53 transcriptional activity. Further immunofluorescence staining, western blotting and reporter assays were performed to elucidate the interaction between KSR1, BRCA1 and p53. Results: KSR1 was expressed with low (60%) and high levels (40%) in breast cancer patients. High expression correlated significantly with longer DFS (p = 0.014) and longer OS (p = 0.012) in more than 20 yrs follow-up. Interestingly, KSR1 was positively associated with BRCA1 (p = 0.002) and reversely with p53 (p = 0.038). High KSR1 levels were a significant predictor of longer breast cancer-specific survival BCSS (p = 0.001) and longer disease free interval DFI (p = 0.002) independent of tumour stage, grade and size. RT-qPCR and western blotting demonstrated that KSR1 is ubiquitously expressed in breast cancer cell lines. In vitro 3D matrigel and soft agar assay showed that MCF7-KSR1 cells had a significant decreased number of colonies and formed smaller size colonies compared to MCF7-vector cells. Furthermore, over-expression of KSR1 (MCF7-KSR1) significantly suppressed the growth of breast cancer xenografts in nude mice. Finally, KSR1 was involved in the functional interaction between BRCA1 and p53 and elevated KSR1 potentially resulted in up-regulated BRCA1. KSR1 also inhibited p53-dependent transcriptional activity through suppression of p53 acetylation and promotion of p53 neddylation. Conclusion: KSR1 is an independent prognostic factor in breast cancer and high KSR1 expression correlates with longer DFS and OS. Furthermore, it is potential that KSR1 is important in tumour suppression by its involvement in functional feedback regulation of BRCA1 and p53. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-04.

Abstract 688: Lamin A/C a novel potential prognostic marker in early operable primary breast cancer

Abstract Background Lamins A/C, a major component of the nuclear lamina of highly differentiated mammalian cells is encoded by LMNA gene. Its involvement in tumorignesis is of interest due to its role in maintaining the nuclear integrity, regulation of gene expression, cell proliferation and apoptosis. Reduced lamin A/C expression in cancer has been reported to be a sign of poor prognosis. However there is few data on its clinical significance in breast cancer. This study aimed to evaluate expression of lamin A/C in a large series of patients with early operable invasive breast cancer; we analyzed the association of lamin A/C expression with clinicopathological parameters and long term clinical outcome. Methods Using immunohistochemistal staining of tissue microarrays, expression of Lamin A/C was evaluated in a large well characterized series of early operable invasive breast carcinoma patients (n=938) obtained from Nottingham Tenovus Primary Breast Carcinoma Series between the period of 1988 and 1998 who underwent primary surgery. All patients were managed following a standard management guidelines by a single team of clinicians and the decision of adjuvant systemic therapy was made on the basis of Nottingham prognostic Index (NPI) score and hormonal status. Using X-tile bioinformatics software a positivity cut-off of H-score &amp;gt;150 was found to be most informative. The expression was then correlated with clinicopathological parameters (age, tumour grade, tumour stage, tumour size, nodal status, vascular invasion, and NPI) using Chi-squared analyses. Association of lamin A/C expression with prognosis [loco-regional recurrence, distant metastasis and breast cancer specific survival (BCSS)] was evaluated by Kaplan Meier survival analysis and Cox proportional hazards model was used to assess the statistical independence and significance of the marker on BCSS. Results The median follow-up of patients was 146 months. Positive expression rate of Lamin A/C was 42.2%. (n=398). Lamin A/C expression was significantly associated with low histological grade (p&amp;lt;0.001), tumour size &amp;lt;1.5 cm (p=0.004), good NPI score (p&amp;lt;0.001), absence of vascular invasion (p=0.014) and absence of distant metastasis (p = 0.027). No association was found between cells expressing lamin A/C and lymph node stage, distant metastases, loco-regional recurrence and patient age. Survival analysis showed that lamin A/C positivity was significantly associated with a longer breast cancer specific survival (p = 0.008) but it was not independent of tumour stage, grade or size for predicting BCSS (p=0.304). Conclusion This study suggests lamin A/C expression as a potential prognostic biomarker for early operable invasive breast cancer. Our findings indicate that lamin A/C expressing tumours are associated with better breast cancer specific survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 688. doi:1538-7445.AM2012-688

FOXO3a nuclear localisation is associated with good prognosis in luminal-like breast cancer

Oestrogen receptor (ER)-positive breast cancer (BC) constitutes a heterogeneous group of tumours with regard to outcome and response to therapy. Accurate stratification of ER-positive BC according to risk of relapse and response to therapy will be achieved through an improved understanding of ER and ER-related biological pathways. Recent studies have identified Forkhead box O3a (FOXO3a) transcription factor as an intracellular mediator of ERα expression and as an important downstream target of the Akt/PI3K pathway indicating a biological and potential clinical role for FOXO3a in ER-positive BC. In this study, we investigated the clinical relevance and biological associations of FOXO3a protein expression, using tissue microarrays and immunohistochemistry, in a large series of patients with invasive breast cancer. FOXO3a protein expression showed both nuclear and/or cytoplasmic staining patterns. FOXO3a predominant nuclear expression was positively associated with biomarkers of good prognosis including PgR, FOXA1 and p27 expression. There was an inverse association with mitotic counts, MIB1 growth fraction, C-MYC and PIK3CA expression. With respect to patient outcome, FOXO3a nuclear localisation was associated with longer BC specific survival (P<0.001) and longer distant metastasis free interval (P=0.001), independently of the well-established breast cancer prognostic factors. In conclusion, our results demonstrate the biological and prognostic role of FOXO3a protein expression and its subcellular localisation in ER-positive/luminal-like BC possibly through its involvement in controlling cell proliferation.

RERG (Ras-like, oestrogen-regulated, growth-inhibitor) expression in breast cancer: a marker of ER-positive luminal-like subtype

Global gene expression profiling studies have classified breast cancer into a number of distinct biological and molecular classes with clinical relevance. The heterogeneous luminal group, which is largely characterised by oestrogen receptor (ER) expression, appears to contain distinct subgroups with differing behaviour. In this study, we analysed 47,293 gene transcripts in 128 invasive breast carcinomas (BC) using Artificial Neural Networks and a cross-validation analysis in combination with an ensemble sample classification to identify genes that can be used to subclassify ER+ luminal tumours. The results were validated using immunohistochemistry on TMAs containing 1,140 invasive breast cancers. Our results showed that the RERG gene is one of the highest ranked genes to differentiate between ER+ luminal-like and ER- non-luminal cancers based on a 10-fold external cross-validation analysis with an average classification accuracy of 89%. This was confirmed in our protein expression studies that showed RERG positive associations with markers of luminal differentiation including ER, luminal cytokeratins (CK19, CK18 and CK7/8) and FOXA1 (P = 0.004) and other markers of good prognosis in BC including small size, lower histologic grade and positive expression of androgen receptor, nuclear BRCA1, FHIT and cell cycle inhibitors p27 and p21. RERG expression was inversely associated with the proliferation marker MIB1 (P = 0.005) and p53. Strong RERG expression showed an association with longer breast cancer specific survival and distant metastasis free interval in the whole series as well as in the ER+ luminal group and these associations were independent of other prognostic variables. In conclusion, we used novel bioinformatics methods to identify candidate genes to characterise ER+ luminal-like breast cancer. RERG gene is a key marker of the luminal BC class and can be used to separate distinct prognostic subgroups.

Growth fraction as a predictor of response to chemotherapy in node‐negative breast cancer

Accurate predictive markers of chemotherapeutic response in early breast cancer are still lacking. The role of tumour growth fraction as a predictor of response to chemotherapy was assessed in early breast cancer. In this study, immunohistochemical expression of MIB1 was studied in a well-characterised series of early (Stages I and II) node-negative breast carcinoma cases (n = 100) with long-term follow-up that have received adjuvant chemotherapy (cyclophosphamide/methotrexate/5-fluorouracil regimen). In addition, 728 cases who did not receive adjuvant chemotherapy were used as a control group. Increased tumour growth fraction was associated with a better response to adjuvant chemotherapy in terms of longer breast cancer specific survival and disease-free interval [hazard ratio (HR) = 0.354, 95% CI = 0.177-0.688, p = 0.003 and HR = 0.396, 95% CI = 0.205-0.768, p = 0.006, respectively]. In contrast to the control group, patients with high growth fraction tumour (>70%) showed an excellent outcome with infrequently reported events during the period of follow-up. Importantly, patients with a low growth fraction (< or =10%) showed frequent recurrences and shorter survival time with outcome comparable to those of high growth fraction who did not receive chemotherapy. Therefore, tumour growth fraction can be used to assign patients into distinct groups showing differential response to adjuvant chemotherapy. Patients with a high growth fraction appear to be ideal candidates for adjuvant chemotherapy while those with low growth fraction are less likely to benefit and are prone to the potential serious side effects of adjuvant chemotherapy.

Prognosis of younger and older patients with early breast cancer.

The use of mammography in recent years has resulted in an increase in the detection of small breast cancers. The beneficial effects of early detection on breast cancer mortality seem to differ with age. To obtain more insight into this matter we studied the long-term prognosis of patients with early invasive breast cancers (T1) in three age groups: 144 patients of age 40-49, 402 patients of age 50-69 and 192 patients 70 years or older at diagnosis. In all age groups, patients with a tumour of 1 cm or less have a longer breast cancer specific survival than patients with a tumour larger than 2 cm. The survival advantage in the case of tumours of a size rounded to 1.5 cm compared with tumours larger than 2 cm in the under age 50 group was marginal (and not significant). However, older patients with tumours of this size do have a significantly improved survival. It is more difficult to improve survival in younger patients through early detection, partly because of an apparent early metastatic potential of their tumours. A reduction in breast cancer mortality might be expected in women younger than 50 years of age only if a substantial proportion of the invasive cancers are detected before their size exceeds 1 cm.