Serum protein profiling reveals an inflammation signature as a predictor of early breast cancer survival.

BACKGROUND: Breast cancers exhibit considerable heterogeneity in their biology, immunology, and prognosis. Currently, no validated, serum protein-based tools are available to evaluate the prognosis of patients with early breast cancer. METHODS: The study population consisted of 521 early-stage breast cancer patients with a median follow-up of 8.9 years. Additionally, 61 patients with breast fibroadenoma or atypical ductal hyperplasia were included as controls. We used a proximity extension assay to measure the preoperative serum levels of 92 proteins associated with inflammatory and immune response processes. The invasive cancers were randomly split into discovery (n = 413) and validation (n = 108) cohorts for the statistical analyses. RESULTS: Using LASSO regression, we identified a nine-protein signature (CCL8, CCL23, CCL28, CSCL10, S100A12, IL10, IL10RB, STAMPB2, and TNFß) that predicted various survival endpoints more accurately than traditional prognostic factors. In the time-dependent analyses, the prognostic power of the model remained rather stable over time. We also developed and validated a 17-protein model with the potential to differentiate benign breast lesions from malignant lesions (Wilcoxon p < 2.2*10- 16; AUC 0.94). CONCLUSIONS: Inflammation and immunity-related serum proteins have the potential to rise above the classical prognostic factors of early-stage breast cancer. They may also help to distinguish benign from malignant breast lesions.

How breast cancer recurrences are found - a real-world, prospective cohort study.

BACKGROUND: There is very limited data available on how most breast cancer recurrences, either distant metastases or locoregional recurrences (LRR), are actually discovered in routine clinical practice. PATIENTS AND METHODS: From a prospective cohort of 621 women diagnosed and treated for early invasive breast cancer between 2003 and 2013, we analysed the patients who were later diagnosed with distant metastases (n = 61) and the patients who had locoregional recurrences (LRR; n = 34). The patients had routine control visits for up to 10 years from initial diagnosis, with annual clinical visits, mammography, blood count, plasma creatinine and liver function tests. RESULTS: Most distant metastases (n = 38, 62%) were found when a patient contacted health care services because of a symptom; only ten (16%) were detected at pre-planned control visits. The most common first sign or symptom of metastasis was pain (n = 23, 38%). Pain as the first indicator of metastasis indicated a lower survival in metastatic disease (hazard ratio 4.40; 95% confidence interval 1.77-10.94; p = 0.001). How relapse was detected or whether patient was symptomatic did not affect overall survival (OS) of patients with distant metastases. LRRs were mostly found at pre-planned control visits (n = 14, 41%). Abnormalities in routine laboratory tests did not lead to any detection of recurrence. DISCUSSION: In this prospective, contemporary, real-world study, the vast majority of both distant metastases and LRRs were detected outside the pre-planned control visits. These results highlight the importance of finding ways to lower the threshold for contacting the surveillance unit, rather than frequent routine controls.

Real-world, single-centre prospective data of age at breast cancer onset: focus on survival and reproductive history.

OBJECTIVES: Being either young or old at the time of breast cancer diagnosis has been suggested as an indicator of a poor prognosis. We studied the effect of age at breast cancer onset in relation to survival, focusing in particular on biological subtypes and reproductive anamnesis. DESIGN, SETTING AND PARTICIPANTS: Patients with early breast cancer (n=594) treated in a Finnish University Hospital during 2003-2013 were prospectively collected and followed in median 102 months. RESULTS: Patients with luminal A-like breast cancer were older than the patients with luminal B-like (HER2-positive) (p=0.045) or patients with the HER2-positive (non-luminal) subtype (p=0.029). Patients ≥70 years received substantially less adjuvant chemotherapy (p=1.5×10-9) and radiotherapy (p=5.9×10-7) than younger women. Nevertheless, the estimated 10-year breast cancer-specific rates of survival were 84.2%, 92.9% and 87.0% in age groups <41 years, 41-69 years and ≥70 years, respectively, with no statistical difference (p=0.115). Survival rates were also comparable between the three age groups when assessed separately in different biological subtypes, and for patients with metastatic breast cancer there was similarly no difference between the age groups. Later menarche (p=5.7×10-8) and high parity (p=0.000078) correlated with increased age at breast cancer diagnosis, but, according to the patients' oestrogen receptor (ER) status, only among ER-positive patients. CONCLUSIONS: Despite the suggested undertreatment of older patients, we report excellent long-term outcomes in all age groups in this prospective cohort. Later endogenous endocrine exposure may cause delay in breast cancer onset, but the exact biology behind this phenomenon is so far unclear.

Prognostic factors in metastatic breast cancer: a prospective single-centre cohort study in a Finnish University Hospital.

OBJECTIVES: Although novel early breast cancer prognostic factors are being continuously discovered, only rare factors predicting survival in metastatic breast cancer have been validated. The prognostic role of early breast cancer prognostic factors in metastatic disease also remains mostly unclear. DESIGN AND SETTING: Prospective cohort study in a Finnish University Hospital. PARTICIPANTS AND OUTCOMES: 594 women with early breast cancer were originally followed. Sixty-one of these patients developed distant metastases during the follow-up, and their primary breast cancer properties, such as tumour size, nodal status, oestrogen receptor (ER) and progesterone receptor expression, grade, proliferation rate, histopathological subtype and breast cancer subtype were analysed as potential prognostic factors for metastatic disease. RESULTS: In multivariate analysis, the presence of lymph node metastases at the time of early breast cancer surgery (HR, 2.17; 95% CI, 1.09-4.31; p=0.027) and ER status (negative vs positive, HR, 2.16; 95% CI, 1.14-4.10; p=0.018) were significant predictors of survival in metastatic disease. CONCLUSIONS: These results confirm ER status as a primary prognostic factor in metastatic breast cancer. Furthermore, it also suggests that the presence of initial lymph node metastases could serve as a prognostic factor in recurrent breast cancer.

High Parity Predicts Poor Outcomes in Patients With Luminal B-Like (HER2 Negative) Early Breast Cancer: A Prospective Finnish Single-Center Study.

While breast cancer prognoses are generally good, different molecular subtypes are known to have varying outcomes. Previous studies using breast cancer registries have suggested that high parity may be an adverse prognostic factor in luminal breast cancer, but breast cancer subtype definitions have varied and there have been few prospective studies. We therefore collected prospective data from patients diagnosed with early breast cancer at a single institution and followed them for a median of 8.5 years. All patients (N = 594) were treated according to Finnish national guidelines using modern treatment modalities in a Finnish university hospital. Clinicopathological surrogates of the intrinsic breast cancer subtypes were updated to match European Society for Medical Oncology 2015 Early Breast Cancer Clinical Practice Guidelines. The overall 10-year breast cancer-specific survival (BCSS) was 91.4%, with the longest 10-year BCSS observed in luminal A-like cancers (97.9%) and the worst in luminal B-like (HER2 positive) cancers (80.6%). Parity of ≥ 5 deliveries was also associated with poor BCSS (univariate P = 0.0020). However, when the subtypes were assessed separately in a multivariate analysis that included tumor size and nodal status, high parity remained significant only in luminal B-like (HER2 negative) cancers (HR = 2.63; 95% confidence interval = 1.04-6.62; P = 0.040). Our results suggest excellent overall 10-year BCSS but indicate that high parity is an adverse prognostic factor in luminal B-like (HER2 negative) breast cancers.

Early progression of breast cancer during neoadjuvant chemotherapy may predict poorer prognoses.

Background: In Finland, breast cancers treated with neoadjuvant chemotherapy (NACT) are usually locally advanced and/or have an inflammatory phenotype. We evaluated early NACT responses in breast tumours and lymph nodes and their correlation with survival.Material and methods: We collected a retrospective dataset of 145 patients with very high-risk but non-metastasised breast cancers that were treated with NACT in a Finnish University Hospital between September 2013 and January 2019. The patients underwent magnetic resonance imaging (MRI) scans before beginning NACT and after every second NACT cycle thereafter.Results: The total pathological complete response rate was only 10.7% and breast cancer-specific survival (BCSS) at 24 months was 93.0%. The 2-year breast cancer-specific survival (BCSS) rate was 93.0%, but this varied from 86.5% for the triple-negative subtype to 100.0% for the luminal A-like subtype. Enlargement of the malignant axillary lymph nodes during the first two NACT cycles was associated with poor BCSS rates in HER2-negative patients (p = .00003 in the univariate analysis; hazard ratio = 26.3; 95% confidence interval = 2.66-259.6; p = .005 in the multivariate analysis). Furthermore, progression in the combined diameters of the breast tumours and axillary lymph nodes during the period between a patient's pre-treatment MRI and her MRI after two NACT cycles was also correlated with worse BCSS rates in both univariate and multivariate analyses.Conclusions: An early MRI assessment after two NACT cycles, specifically of the tumour's axillary lymph nodes, has the potential to predict short-term BCSS in patients with locally advanced HER2-negative breast cancers.

Cytoplasmic Mineralocorticoid Receptor Expression Predicts Dismal Local Relapse-free Survival in Non-triple-negative Breast Cancer.

BACKGROUND/AIM: The aim of the study was to investigate the prognostic role of androgen receptor (AR), mineralocorticoid receptor (MR) and glucocorticoid receptor ß (GRß) expression in HER-2 negative breast cancer patients. MATERIALS AND METHODS: The study population (n=152) was enriched with triple-negative breast cancers (TNBC) (n=96; 63.2%). The median follow-up time was 100 months. AR, MR and GRß immunocytochemical staining was compared with that of epithelial-mesenchymal transition (EMT) markers (vimentin, SIP1, ZEB1). RESULTS: High expression of cytoplasmic MR was associated with dismal local relapse-free survival (RR=13.923; 95%CI=1.071-181.045; p=0.044) in tumours with non-TNBC phenotype. AR and GRß were more frequently expressed in ER+/PR+/HER2- tumours, while cytoplasmic MR was more often expressed in TNBC tumours (for all, p<0.0005). GRß and AR were associated with decreased vimentin expression (p<0.005), indicating their association with attenuated EMT. CONCLUSION: Cytoplasmic MR expression is a strong predictor of local recurrence in non-metastatic breast cancer patients with non-TNBC tumour phenotype.

Elevated preoperative serum levels of collagen I carboxyterminal telopeptide predict better outcome in early-stage luminal-B-like (HER2-negative) and triple-negative subtypes of breast cancer.

Type 1 collagen is an important part of the extracellular matrix and changes in its metabolism and distribution are essential in breast cancer induction and progression. Serum concentrations of type 1 collagen synthesis (aminoterminal propeptide (PINP)) and degradation markers (carboxyterminal telopeptide (ICTP)) have previously been studied in early and metastatic breast cancer, but no data are available on specific breast cancer subtypes. We assayed 662 preoperative serum samples for PINP and ICTP and 109 postoperative serum samples for ICTP. The results were linked to prospectively collected clinical data and the cases were divided into breast cancer subtypes for survival analyses. The concentrations of both pre- and postoperative ICTP serum levels increased linearly from ductal in situ carcinoma to stage I-II tumors, stage III tumors, and finally to those with concomitant primary metastases (preoperative ICTP, p = 0.009; postoperative ICTP, p = 0.016). High-preoperative ICTP levels were associated with better breast cancer-specific survival in connection with luminal-B-like (HER2-negative) tumors (p = 0.017), which was confirmed in Cox regression analysis (relative risk = 3.127; 95% confidence interval = 1.081-9.049, p = 0.035), when T-class (relative risk = 4.049; 95% confidence interval = 1.263-12.981; p = 0.019) and nodal status (relative risk = 3.896; 95% confidence interval = 1.088-13.959; p = 0.037) were included in the analysis. In patients with triple-negative breast cancer, a high-preoperative ICTP level was a significant predictor of local relapse-free survival in univariate (p = 0.0020) and multivariate analyses (relative risk = 13.04; 95% confidence interval = 1.354-125.5; p = 0.026; for T-class, relative risk = 2.128 and 95% confidence interval = 0.297-15.23; p = 0.452; for N-class, relative risk = 0.332 and 95% confidence interval = 0.033-3.307; p = 0.347). A preoperatively elevated serum ICTP level appears to be an important marker of better prognosis in triple-negative breast cancer and luminal-B-like (HER2-negative) subtypes.

High-level cytoplasmic claudin 3 expression is an independent predictor of poor survival in triple-negative breast cancer.

BACKGROUND: The subtype of claudin-low breast cancer can be reliably determined only by gene-expression profiling. Attempts have been made to develop immunohistochemical surrogates, which nearly always focus on membranous claudin expression. METHODS: We assessed the immunohistochemical expression of both membranous and cytoplasmic claudins 3, 4 and 7 in a series of 197 non-metastatic breast cancers, enriched with triple-negative breast cancers (TNBCs; 60%). The expression of epithelial-to-mesenchymal transition-regulating transcription factors Sip1, Zeb1 and vimentin had previously been determined in the same material. RESULTS: In multivariate analysis, strong cytoplasmic claudin 3 expression was associated with poor relapse-free survival (RFS), disease-free survival, distant disease-free survival, breast cancer-specific survival and overall survival among TNBC patients (for RFS, RR 5.202, 95% CI 1.210-22.369, p = 0.027, vs. T-class, RR 0.663, 95% CI 0.168-2.623, p = 0.558, and N-class, RR 3.940, 95% CI 0.933-16.631, p = 0.062). Cytoplasmic claudin 3 expression was also associated with strong nuclear Sip1 expression (p = 0.000053), TNBC phenotype (p = 0.012) and within them, non-basal-like phenotype (p = 0.026). Cytoplasmic claudin 7 was associated with dismal RFS (RR 6.328, 95% CI 1.401-28.593, p = 0.016, vs. T-class, RR 0.692, 95% CI 0.242-1.982, p = 0.493, and N-class, RR 2.981, 95% CI 1.1016-8.749, p = 0.047). Low cytoplasmic expression of claudins 3, 4 and 7 together also predicted poor RFS (RR 6.070, 95% CI 1.347-27.363, p = 0.019, vs. T-class, RR 0.677, 95% CI 0.237-1.934, p = 0.467, and N-class, RR 3.167, 95% CI 1.079-9.290, p = 0.036). CONCLUSIONS: Immunohistochemical expression levels of cytoplasmic claudins 3 and 7 appear to be novel prognostic factors in TNBC.