Trastuzumab and first-line taxane chemotherapy in metastatic breast cancer patients with a HER2-negative tumor and HER2-positive circulating tumor cells: a phase II trial.

PURPOSE: HER2 overexpressing circulating tumor cells (CTCs) are observed in up to 25% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically improved clinical outcomes of patients with HER2-positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy. METHODS: In this single-arm, phase II trial, patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy. Patients with detectable CTCs but without HER2 overexpression that received taxane chemotherapy only, were used as control group. The primary outcome measure was progression-free rate at 6 months (PFR6), with a target of 80%. In November 2022, the study was terminated early due to slow patient accrual. RESULTS: 63 patients were screened, of which eight patients had HER2-positive CTCs and were treated with trastuzumab. The median number of CTCs was 15 per 7.5 ml of blood (range 1-131) in patients with HER2-positive CTCs, compared to median 5 (range 1-1047) in the control group. PFR6 was 50% in the trastuzumab group and 54% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p = 0.51). CONCLUSION: No clinical benefit of trastuzumab was observed, although this study was performed in a limited number of patients. Additionally, we observed a strong correlation between the number of evaluable CTCs and the presence of HER2-positive CTCs. We argue that randomized studies investigating agents that are proven to be solely effective in the HER2-positive patient group in patients with HER2-positive CTCs and HER2-negative tissue are currently infeasible. Several factors contribute to this impracticality, including the need for more stringent thresholds, and the rapidly evolving landscape of cancer treatments.

Androgen receptor expression in circulating tumor cells of patients with metastatic breast cancer.

The androgen receptor (AR) has potential clinical relevance in metastatic breast cancer (mBC) since it might be a treatment target and has been associated with endocrine resistance. A minimal-invasive way to determine AR expression on metastatic tumor cells is by characterization of circulating tumor cells (CTCs). Here, we assessed AR mRNA expression in CTCs (CTC-AR) and in matched primary tumor samples from mBC patients representing different breast cancer subtypes. In addition, we explored CTC-AR-status in relation to outcome on endocrine therapy. AR, and 92 AR or estrogen receptor (ER) related genes, were measured in CellSearch-enriched CTCs from 124 mBC patients and in 52 matched FFPE primary tissues using quantitative reverse-transcriptase PCR. AR in CTCs was considered positive if the expression was 1 standard deviation higher than the expression measured in 11 healthy blood donors. A total of 31% of the mBC patients had AR-positive (AR+) CTCs. 58% of the matched CTC and primary tumor samples were discordant with respect to AR status, observing both switches from AR+ to AR-negative (AR-) and vice versa. There was no statistically significant difference in progression-free survival for patients treated with ER-targeting drugs and CTC-AR-status (13 AR+/ 37 AR- cases, p = 0.28). Thus, AR can be determined in RNA isolated from CTCs, with in our set 31% AR-positive samples. Given the discordance between AR status in CTC samples and corresponding primary tumors, determination of AR expression in CTCs might be a promising tool to select mBC patients for AR inhibiting agents.

Liquid Biopsies to Select Patients for Perioperative Chemotherapy in Muscle-invasive Bladder Cancer: A Systematic Review.

CONTEXT: Neoadjuvant chemotherapy (NAC) is considered the standard treatment for muscle-invasive bladder cancer (MIBC). However, its overall survival benefit is limited and toxicity is significant; hence, NAC has not been adopted universally. OBJECTIVE: To systematically evaluate whether biomarkers can guide the administration of perioperative chemotherapy in MIBC patients. EVIDENCE ACQUISITION: A systematic search of the PubMed database was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). In total, 215 papers were screened and 22 were selected to assess the potential clinical value of circulating tumor cells (CTCs) and cell-free DNA (cfDNA) in selecting MIBC patients for perioperative chemotherapy. EVIDENCE SYNTHESIS: We found that the presence of one or more CTCs before radical cystectomy, as determined by the CellSearch technique, is a robust marker for poor recurrence-free and overall survival. Consequently, whether NAC can be withheld in patients without the presence of CTCs is a subject of ongoing investigation. Studies investigating various approaches to detect cfDNA showed that cfDNA is present in the blood of MIBC patients, but varying results on its prognostic value have been reported. Successful cfDNA-based approaches are likely to encompass at least a multitude of genes using next-generation sequencing, as there are generally few hotspot somatic mutations in MIBC. CONCLUSIONS: Liquid biopsies hold promise in selecting MIBC patients for perioperative chemotherapy, but instead of more proof-of-principle studies, prospective studies investigating true clinical applicability for treatment decision making are urgently needed. PATIENT SUMMARY: Liquid biopsies appear to be a promising tool to guide the administration of chemotherapy in patients with muscle-invasive bladder cancer; however, the optimal way to implement these remains to be determined.

Circulating Tumor Cell Enumeration and Characterization in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Cabazitaxel.

(1) Background: Markers identifying which patients with metastatic, castration-resistant prostate cancer (mCRPC) will benefit from cabazitaxel therapy are currently lacking. Therefore, the aim of this study was to identify markers associated with outcome to cabazitaxel therapy based on counts and gene expression profiles of circulating tumor cells (CTCs). (2) Methods: From 120 mCRPC patients, CellSearch enriched CTCs were obtained at baseline and after 6 weeks of cabazitaxel therapy. Furthermore, 91 genes associated with prostate cancer were measured in mRNA of these CTCs. (3) Results: In 114 mCRPC patients with an evaluable CTC count, the CTC count was independently associated with poor progression-free survival (PFS) and overall survival (OS) in multivariable analysis with other commonly used variables associated with outcome in mCRPC (age, prostate specific antigen (PSA), alkaline phosphatase, lactate dehydrogenase (LDH), albumin, hemoglobin), together with alkaline phosphatase and hemoglobin. A five-gene expression profile was generated to predict for outcome to cabazitaxel therapy. However, even though this signature was associated with OS in univariate analysis, this was not the case in the multivariate analysis for OS nor for PFS. (4) Conclusion: The established five-gene expression profile in CTCs was not independently associated with PFS nor OS. However, along with alkaline phosphatase and hemoglobin, CTC-count is independently associated with PFS and OS in mCRPC patients who are treated with cabazitaxel.

The Prevalence of CD146 Expression in Breast Cancer Subtypes and Its Relation to Outcome.

CD146, involved in epithelial-to-mesenchymal transition (EMT), might affect cancer aggressiveness. We here investigated the prevalence of CD146 expression in breast cancer subtypes, its relation to prognosis, the relation between CD146 and EMT and the outcome to tamoxifen. Primary breast cancer tissues from 1342 patients were available for this retrospective study and immunohistochemically stained for CD146. For survival analyses, pure prognosis was studied by only including lymph-node negative patients who did not receive (neo)adjuvant systemic treatment (n = 551). 11% of the tumors showed CD146 expression. CD146 expression was most prevalent in triple-negative cases (64%, p < 0.001). In univariable analysis, CD146 expression was a prognostic factor for both metastasis-free survival (MFS) (p = 0.020) and overall survival (OS) (p = 0.037), but not in multivariable analysis (including age, tumor size, grade, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67). No correlation between CD146 and EMT nor difference in outcome to first-line tamoxifen was seen. In this large series, our data showed that CD146 is present in primary breast cancer and is a pure prognostic factor for MFS and OS in breast cancer patients. We did not see an association between CD146 expression and EMT nor on outcome to tamoxifen.