Circulating tumor DNA for predicting recurrence in patients with operable breast cancer: a systematic review and meta-analysis.

BACKGROUND: The incorporation of circulating tumor DNA (ctDNA) into the management of operable breast cancer (BC) has been hampered by the heterogeneous results from different studies. We aimed to assess the prognostic value of ctDNA in patients with operable (non metastatic) BC. MATERIALS AND METHODS: A systematic search of databases (PubMed/Medline, Embase, and CENTRAL) and conference proceedings was conducted to identify studies reporting the association of ctDNA detection with disease-free survival (DFS) and overall survival (OS) in patients with stage I-III BC. Log-hazard ratios (HRs) were pooled at each timepoint of ctDNA assessment (baseline, after neoadjuvant therapy, and follow-up). ctDNA assays were classified as primary tumor-informed and non tumor-informed. RESULTS: Of the 3174 records identified, 57 studies including 5779 patients were eligible. In univariate analyses, ctDNA detection was associated with worse DFS at baseline [HR 2.98, 95% confidence interval (CI) 1.92-4.63], after neoadjuvant therapy (HR 7.69, 95% CI 4.83-12.24), and during follow-up (HR 14.04, 95% CI 7.55-26.11). Similarly, ctDNA detection at all timepoints was associated with worse OS (at baseline: HR 2.76, 95% CI 1.60-4.77; after neoadjuvant therapy: HR 2.72, 95% CI 1.44-5.14; and during follow-up: HR 9.19, 95% CI 3.26-25.90). Similar DFS and OS results were observed in multivariate analyses. Pooled HRs were numerically higher when ctDNA was detected at the end of neoadjuvant therapy or during follow-up and for primary tumor-informed assays. ctDNA detection sensitivity and specificity for BC recurrence ranged from 0.31 to 1.0 and 0.7 to 1.0, respectively. The mean lead time from ctDNA detection to overt recurrence was 10.81 months (range 0-58.9 months). CONCLUSIONS: ctDNA detection was associated with worse DFS and OS in patients with operable BC, particularly when detected after treatment and using primary tumor-informed assays. ctDNA detection has a high specificity for anticipating BC relapse.

Prognostic value of HER2-low status in breast cancer: a systematic review and meta-analysis.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low expression in breast cancer has been recently identified as a new therapeutic target. However, it is unclear if HER2-low status has an independent impact on prognosis. MATERIALS AND METHODS: A systematic literature research was carried out to identify studies comparing survival outcomes of patients affected by HER2-low versus HER2-zero breast cancer. Using random-effects models, pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for progression-free survival (PFS) and overall survival (OS) in the metastatic setting as well as disease-free survival (DFS), OS and pathological complete response (pCR) in the early setting. Subgroup analyses by hormone receptor (HoR) status were carried out. The study protocol is registered on PROSPERO (n.CRD42023390777). RESULTS: Among 1916 identified records, 42 studies including 1 797 175 patients were eligible. In the early setting, HER2-low status was associated with significant improved DFS (HR 0.86, 95% CI 0.79-0.92, P < 0.001) and OS (HR 0.90, 95% CI 0.85-0.95, P < 0.001) when compared to HER2-zero status. Improved OS was observed for both HoR-positive and HoR-negative HER2-low populations, while DFS improvement was observed only in the HoR-positive subgroup. HER2-low status was significantly associated with a lower rate of pCR as compared to HER2-zero status both in the overall population (OR 0.74, 95% CI 0.62-0.88, P = 0.001) and in the HoR-positive subgroup (OR 0.77, 95% CI 0.65-0.90, P = 0.001). In the metastatic setting, patients with HER2-low breast cancers showed better OS when compared with those with HER2-zero tumours in the overall population (HR 0.94, 95% CI 0.89-0.98, P = 0.008), regardless of HoR status. No significant PFS differences were found. CONCLUSIONS: Compared with HER2-zero status, HER2-low status appears to be associated with a slightly increased OS both in the advanced and early settings, regardless of HoR expression. In the early setting, HER2-low tumours seem to be associated to lower pCR rates, especially if HoR-positive.

Efficacy of tyrosine kinase inhibitors for the treatment of patients with HER2-positive breast cancer with brain metastases: a systematic review and meta-analysis.

BACKGROUND: Brain metastases (BMs) are frequent events in patients with HER2-positive metastatic breast cancer (MBC) and are associated with poor prognosis. Small-molecule anti-HER2 tyrosine kinase inhibitors (TKIs) are promising agents for the treatment of BM. In this study, we assess the clinical outcomes of patients with HER2-positive MBC and BM treated with TKI-containing regimens compared with those treated with non-TKI-containing regimens. MATERIALS AND METHODS: PubMed, Embase, Cochrane Library, and conference proceedings (ASCO, SABCS, ESMO, and ESMO Breast) were searched up to June 2021. The primary endpoint was progression-free survival (PFS) in patients with BM. Secondary endpoints included PFS in patients without BM and overall survival (OS). The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Overall effects were pooled using random-effects models. RESULTS: This systematic review and meta-analysis included data from 2437 patients (490 with and 1947 without BM at baseline) enrolled in five trials assessing tucatinib-, lapatinib-, pyrotinib-, or afatinib-based combinations. A nonstatistically significant PFS benefit favoring TKI-containing regimens was observed in both patients with BM [hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.41-1.12; P = 0.13] and without BM (HR 0.55, 95% CI 0.24-1.26; P = 0.16). Sensitivity analysis, excluding each study singly, demonstrated a significant PFS benefit favoring TKI-containing regimens in patients with BM after the exclusion of afatinib from the analysis (HR 0.56, 95% CI 0.35-0.90; P = 0.016). No statistically significant differences in OS were observed between the comparison groups. CONCLUSIONS: A trend in PFS favoring TKI-containing regimens was observed in patients with BM. Sensitivity analysis including only trials that evaluated regimens containing tucatinib, lapatinib, or pyrotinib demonstrated a significant PFS benefit favoring TKI-containing regimens in patients with BM.

How we treat patients with metastatic HER2-positive breast cancer.

HER2-positive breast cancer represents 15%-20% of breast malignancies and is characterized by an aggressive behavior and high recurrence rates. Anti-HER2-directed agents represent the mainstay of treatment of patients with HER2-positive metastatic breast cancer (MBC). In this review we propose a treatment algorithm for patients with HER2-positive MBC based on the currently available literature on the topic. The combination of trastuzumab, pertuzumab and a taxane (THP) remains the preferred first-line therapy in most scenarios. Results of trials recently presented at the European Society for Medical Oncology (ESMO) Congress 2021 might have direct clinical impact in the second- and later-line settings. The randomized DESTINY-BREAST03 study compared trastuzumab deruxtecan (T-DXd) with trastuzumab emtansine (T-DM1) in patients previously treated with trastuzumab and a taxane. T-DXd significantly improved progression-free survival and showed a trend towards improved overall survival, establishing this agent as preferred second-line therapy. Treatment with T-DM1, or the combination of tucatinib, trastuzumab and capecitabine, are considered reasonable options after second-line therapy. For subsequent lines, trastuzumab duocarmazine, neratinib plus capecitabine or the continuation of trastuzumab with different chemotherapy partners are valid options. For patients experiencing disease relapse up to 6 months after completion of adjuvant therapy, as well as for those relapsing within 12 months from the completion of pertuzumab-based adjuvant treatment, we recommend T-DXd as preferred first-line option. For those relapsing between 6 and 12 months after non-pertuzumab-based adjuvant treatment, we recommend first-line THP. Finally, for patients with active brain metastasis, tucatinib-based combination represents a suitable second-line option.