Tumor mutational burden (TMB) and density of tumor-infiltrating lymphocytes (TIL) have been postulated as predictive biomarkers for immunotherapy. Therefore, we investigated the concordance of TMB ...and TIL of primary/extracranial renal cell carcinoma (RCC) specimens and matched brain metastases (BM).
Twenty specimens from 10 patients were retrieved from the Vienna Brain Metastasis Registry (6/10 primary tumor, 4/10 lung metastasis, 10/10 matched BM). TMB was assessed using the TruSight Oncology 500 gene panel with libraries sequenced on a NextSeq instrument. TIL subsets (CD3+, CD8+, CD45RO+, FOXP3+, PD-L1+) were investigated using immunohistochemistry (Ventana Benchmark Ultra system) and automated tissue analysis (Definiens software).
No significant difference in TMB, CD3+, CD8+, CD45RO+, FOXP3+ or PD-L1+ expression was observed between extracranial and matched intracranial specimens (P > 0.05). Higher CD8+ TIL (P = 0.053) and CD45RO+ TIL (P = 0.030) densities in the primary tumor compared with the intracranial samples were observed in specimens collected after exposure to systemic treatment. Neither extracranial sample origin (lung metastasis versus primary RCC) nor extracranial disease status at BM diagnosis (progressive versus stable disease) were significantly associated with TMB or TIL densities in extracranial and intracranial samples (P > 0.05). No significant correlation was found between the median differences of TMB or TIL densities from extracranial to intracranial samples and BM-free survival.
The comparable immunological microenvironment of extra- and intracranial tumor samples in our study underscores the immunological activation also in BM from RCC, and therefore, supports the development of immune modulatory treatments also in patients with brain metastatic RCC.
•Immunological microenvironment characteristics were comparable in extra- and intracranial RCC samples.•Numerically higher CD45RO+ and CD8+ TIL densities in extracranial compared to intracranial samples after systemic therapy.•The inflammatory microenvironment is a promising therapeutic target in RCC BM.
Abstract Background Recently, HER3-expression was postulated as independent risk factor for metastatic spread. Therefore, we investigated the role of HER3 expression as prognostic marker in ...metastatic breast cancer patients. Methods Patients of different breast cancer subtypes diagnosed with metastatic disease (visceral and/or brain metastases) were identified from a breast cancer database. Tissue samples of the respective primary tumors were retrieved, and immunohistochemical staining for estrogen-receptor, progesterone-receptor, HER2, and HER3 was performed. In HER2 equivocal and selected HER3 positive cases, subsequent fluorescent in situ hybridization (FISH) analysis was performed. Results Tissue specimens of 110 patients were available for this analysis. 21% had strong, complete, membranous HER3 staining of at least 10% of all tumor cells; HER3 protein expression was not associated with HER3 gene amplification. HER2/HER3 co-overexpression was observed in 12/110 (11%) specimens and HER3-overexpression showed a statistically significant association with HER2-overexpression ( p = 0.02). No correlation was observed for HER3-overexpression and overall survival (OS), time to diagnosis of brain metastases, and incidence of brain metastases. Still, in patients with HER3 overexpression, a higher rate of ‘brain only’ metastatic behavior was observed ( p = 0.042). In the HER2-positive subgroup, HER3-overexpression was significantly associated with shorter OS from diagnosis of metastatic disease (median 17 vs. 35 months; p = 0.04; log rank test). Conclusions HER2/HER3 co-overexpression is significantly associated with impaired OS from diagnosis of metastatic disease in patients with HER2-positive metastatic breast cancer. Co-inhibition of HER2 and HER3 or the inhibition of HER2/HER3 hetero-dimerization may improve clinical outcome in this subgroup.
The clinical course of breast cancer patients with brain metastases (BM) as only metastatic site (brain-only metastatic breast cancer (BO-MBC)) has been insufficiently explored.
All breast cancer ...patients with BM treated at our institution between 1990 and 2011 were identified. For each patient, full information on follow-up and administered therapies was mandatory for inclusion. Oestrogen receptor, progesterone receptor and Her2 status were determined according to standard protocols. Statistical analyses including computation of survival probabilities was performed.
In total, 222 female patients (26% luminal; 47% Her2; 27% triple negative) with BM of MBC were included in this study. In all, 38/222 (17%) BM patients did not develop extracranial metastases (ECM) during their disease course and were classified as BO-MBC. Brain-only-MBC was not associated with breast cancer subtype or number of BM. The median overall survival of BO-MBC patients was 11 months (range 0-69) and was significantly longer than in patients with BM and ECM (6 months, range 0-104; P=0.007). In all, 7/38 (18%) BO-MBC patients had long-term survival of >3 years after diagnosis of BM and long-term survival was significantly more common in BO-MBC patients as compared with BM patients with ECM (P<0.001).
Brain-only metastatic behaviour occurs in around 17% of breast cancer with BM and is not associated with breast cancer subtype. Exploitation of all multimodal treatment options is warranted in BO-MBC patients, as these patients have favourable prognosis and long-term survival is not uncommon.
Brain metastases (BM) are a rare complication in colorectal cancer (CRC) patients and associated with an unfavorable survival prognosis. Primary tumor side (PTS) was shown to act as a prognostic and ...predictive biomarker in several trials including metastatic CRC (mCRC) patients. Here, we aim to investigate whether PTS is also associated with the outcome of CRC patients with BM.
Patients treated for CRC BM between 1988 and 2017 at an academic care center were included. Right-sided CRC was defined as located in the appendix, cecum and ascending colon and left-sided CRC was defined as located in the descending colon, sigma and rectum.
Two hundred and eighty-one CRC BM patients were available for this analysis with 239/281 patients (85.1%) presenting with a left-sided and 42/281 patients (14.9%) with a right-sided primary CRC. BM-free survival (BMFS) was significantly longer in left-sided compared with right-sided CRC patients (33 versus 20 months, P = 0.009). Overall survival from CRC diagnosis as well as from diagnosis of BM was significantly longer in patients with a left-sided primary (42 versus 25 months, P = 0.002 and 5 versus 4 months, P = 0.005, respectively). In a multivariate analysis including graded prognostic assessment, PTS remained significantly associated with prognosis after BM (hazard ratio 0.65; 95% confidence interval: 0.46-0.92 months, P = 0.0016).
PTS was associated with survival times after the rare event of BM development in CRC patients. Therefore, its prognostic value remains significant even thereafter.
•Primary tumor side is a relevant and independent prognostic factor in mCRC.•Left-sided CRC was associated with a significantly longer BMFS compared with right-sided CRC.•OS from initial diagnosis of CRC as well as from BM was significantly longer in patients with left-sided primaries.
Symptomatic brain metastases (BM) are a frequent and late complication in cancer patients. However, a subgroup of cancer patients presents with BM as the first symptom of metastatic cancer. Here we ...aimed to analyze the clinical course and prognostic factors of this particular BM patient population. Patients presenting with newly diagnosed BM without a history of metastatic cancer were identified from the Vienna Brain Metastasis Registry. Clinical characteristics and overall survival were retrieved by chart review. 459/2419 (19.0%) BM patients presented with BM as first symptom of advanced cancer. In 374/459 (81.5%) patients, an extracranial primary tumor, most commonly lung cancer, could be identified within 3 months after BM diagnosis. In 85/459 (18.5%) patients no extracranial primary tumor could be identified despite comprehensive diagnostic workup within the first 3 months after diagnosis of BM. Survival of patients with identified extracranial tumor differed only numerically from patients with cancer of unknown primary (CUP), however patients receiving targeted therapy after molecular workup showed significantly enhanced survival (20 months vs. 7 months; p = 0.003; log rank test). The GPA score showed a statistically significant association with median overall survival times in the CUP BM patients (class I: 46 months; class II: 7 months; class III: 4 months; class IV: 2 months; p < 0.001; log rank test). The GPA score has a strong prognostic value in patients with CUP BM and may be useful for patient stratification in the clinical setting. Comprehensive diagnostic workup including advanced imaging techniques and molecular tissue analyses appears to benefit patients by directing specific molecular targeted therapies.
Trastuzumab-based therapy after diagnosis of brain metastases (BM) may improve survival due to prolonged systemic disease control. We investigated whether lapatinib may yield additional survival ...benefit.
Eighty patients with BM from HER2-positive breast cancer were identified. Karnofsky Performance Score (KPS) of at least 70 was required. We included a control group of 37 patients treated before 2003, when continuation of trastuzumab after diagnosis of BM was not yet recommended. Remainders received either trastuzumab or lapatinib and trastuzumab (either concomitantly or sequentially) with or without chemotherapy.
Median overall survival (OS) in patients receiving trastuzumab after diagnosis of BM was 13 months; corresponding numbers were 9 months in patients treated with chemotherapy, and 3 months with radiotherapy alone. Median OS was not reached in the lapatinib group. Addition of lapatinib prolonged OS over trastuzumab alone (P=0.002). After correction for potential confounders, lapatinib therapy remained an independent positive predictor for survival (HR 0.279; P=0.012).
This retrospective single-centre study suggests that the introduction of lapatinib improved survival in patients with BM from HER2-positive breast cancer. Patients with KPS ≥70 may benefit when treated with lapatinib in addition to trastuzumab after completion of local therapy.
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