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Background: Remodeling of extracellular matrix through collagen degradation is a crucial step in the metastatic cascade. The aim of this study was to evaluate the potential clinical relevance of the serum collagen degradation markers (CDM) C3M and C4M during neoadjuvant chemotherapy for breast cancer.
Methods: Patients from the GeparQuinto phase 3 trial with untreated HER2-positive operable or locally advanced breast cancer were enrolled between 7 November 2007, and 9 July 2010, and randomly assigned to receive neoadjuvant treatment with EC/docetaxel with either trastuzumab or lapatinib. Blood samples were collected at baseline, after four cycles of chemotherapy and at surgery. Cutoff values were determined using validated cutoff finder software (C3M: Low ≤9.00 ng/mL, high >9.00 ng/mL, C4M: Low ≤40.91 ng/mL, high >40.91 ng/mL).
Results: 157 patients were included in this analysis. At baseline, 11.7% and 14.8% of patients had high C3M and C4M serum levels, respectively. No correlation was observed between CDM and classical clinical-pathological factors. Patients with high levels of CDM were significantly more likely to achieve a pathological complete response (pCR, defined as ypT0 ypN0) than patients with low levels (C3M: 66.7% vs. 25.7%, p = 0.002; C4M: 52.7% vs. 26.6%, p = 0.031). Median levels of both markers were lower at the time of surgery than at baseline. In the multivariate analysis including clinical-pathological factors and C3M levels at baseline and changes in C3M levels between baseline and after four cycles of therapy, only C3M levels at baseline (p = 0.035, OR 4.469, 95%-CI 1.115–17.919) independently predicted pCR. In a similar model including clinical-pathological factors and C4M, only C4M levels at baseline (p = 0.028, OR 6.203, 95%-CI 1.220–31.546) and tumor size (p = 0.035, OR 4.900, 95%-CI 1.122–21.393) were independent predictors of pCR. High C3M levels at baseline did not correlate with survival in the entire cohort but were associated with worse disease-free survival (DFS; p = 0.029, 5-year DFS 40.0% vs. 74.9%) and overall survival (OS; p = 0.020, 5-year OS 60.0% vs. 88.3%) in the subgroup of patients randomized to lapatinib. In the trastuzumab arm, C3M did not correlate with survival. In the entire patient cohort, high levels of C4M at baseline were significantly associated with shorter DFS (p = 0.001, 5-year DFS 53.1% vs. 81.6%) but not with OS. When treatment arms were considered separately, the association with DFS was still significant (p = 0.014, 5-year DFS 44.4% vs. 77.0% in the lapatinib arm; p = 0.023, 5-year DFS 62.5% vs. 86.2% in the trastuzumab arm).
Conclusions: Collagen degradation markers are associated with response to neoadjuvant therapy and seem to play a role in breast cancer.
Background: The incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear.
Methods: We analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy.
Results: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease.
In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3–4; HR 1.63, 95% CI 1.08–2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64–4.04, p < 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32–3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89–7.64, p < 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28–12.44, p < 0.001).
Conclusions: Especially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies.