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Historically, studies of disseminated tumour cells in bone marrow and circulating tumour cells in peripheral blood have provided crucial insights into cancer biology and the metastatic process. More recently, advances in the detection and characterization of circulating tumour DNA (ctDNA) have finally enabled the introduction of liquid biopsy assays into clinical practice. The FDA has already approved several single-gene assays and, more recently, multigene assays to detect genetic alterations in plasma cell-free DNA (cfDNA) for use as companion diagnostics matched to specific molecularly targeted therapies for cancer. These approvals mark a tipping point for the widespread use of liquid biopsy in the clinic, and mostly in patients with advanced-stage cancer. The next frontier for the clinical application of liquid biopsy is likely to be the systemic treatment of patients with ‘ctDNA relapse’, a term we introduce for ctDNA detection prior to imaging-detected relapse after curative-intent therapy for early stage disease. Cancer screening and diagnosis are other potential future applications. In this Perspective, we discuss key issues and gaps in technology, clinical trial methodologies and logistics for the eventual integration of liquid biopsy into the clinical workflow.Liquid biopsy assays have the potential to revolutionize the diagnosis and management of cancer, and rapid progress is being made in the clinical translation of such assays. This Perspective outlines notable advances in the use of liquid biopsy technologies in the management of solid tumours, as well as future research avenues, clinical trial methodologies and implementation logistics for the eventual integration of liquid biopsy into the clinical workflow.

Following the first characterization of circulating tumor DNA (ctDNA) in the 1990s, recent advances led to its introduction in the clinics. At present, the European Society Of Medical Oncology (ESMO) recommendations endorse ctDNA testing in routine clinical practice for tumor genotyping to direct molecularly targeted therapies in patients with metastatic cancer. In studies on metastatic breast cancer, ctDNA has been utilized for treatment tailoring, tracking mechanisms of drug resistance, and for predicting disease response before imaging. We review the available evidence regarding ctDNA applications in metastatic breast cancer.

Whole-genome and targeted sequencing of multiple sections of each of 50 tumors reveals varying degrees of subclonal diversification and genomic heterogeneity. The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA , TP53 , PTEN, BRCA2 and MYC , occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.

While triple-negative breast cancer (TNBC) is known to be heterogeneous at the genomic and transcriptomic levels, spatial information on tumor organization and cell composition is still lacking. Here, we investigate TNBC tumor architecture including its microenvironment using spatial transcriptomics on a series of 92 patients. We perform an in-depth characterization of tumor and stroma organization and composition using an integrative approach combining histomorphological and spatial transcriptomics. Furthermore, a detailed molecular characterization of tertiary lymphoid structures leads to identify a gene signature strongly associated to disease outcome and response to immunotherapy in several tumor types beyond TNBC. A stepwise clustering analysis identifies nine TNBC spatial archetypes, further validated in external datasets. Several spatial archetypes are associated with disease outcome and characterized by potentially actionable features. In this work, we provide a comprehensive insight into the complexity of TNBC ecosystem with potential clinical relevance, opening avenues for treatment tailoring including immunotherapy. Triple-negative breast cancer (TNBC) is a heterogenous disease with several molecular subtypes previously described. Here the authors perform a spatial transcriptomics analysis on a series of 92 patients, providing additional insights into the heterogeneity of TNBC, with implications for clinical outcomes and therapy.

Chemo-immunotherapy is the first-line standard of care for patients with PD-L1 positive metastatic triple-negative breast cancer (mTNBC). SYNERGY (NCT03616886) is a dose-finding phase I and a randomized phase II, open-label trial evaluating if targeting the immunosuppressive adenosine pathway can enhance the antitumor activity of chemo-immunotherapy. The phase I part included 6 patients with untreated locally-advanced or mTNBC to determine the safety and recommended phase II dose of the anti-CD73 antibody oleclumab in combination with the anti-PD-L1 durvalumab and 12 cycles of weekly carboplatin and paclitaxel. In the phase II part, 127 women were randomized 1:1 to receive chemo-immunotherapy, with (arm A) or without (arm B) oleclumab. The primary endpoint was the clinical benefit rate at week 24, defined as stable disease, partial or complete response per RECIST v1.1. Secondary endpoints included objective response rate, duration of response, survival outcomes (progression-free survival and overall survival), and safety. The trial did not meet its primary endpoint, as the 24-week clinical benefit rate was not significantly improved by adding oleclumab (43% vs. 44%, p  = 0.61). Exploratory median progression-free survival was 5.9 months in arm A as compared to 7.0 months in arm B ( p  = 0.90). The safety profile was manageable in both arms. Preclinical studies have shown that blockade of the CD73-adenosinergic pathway could improve anti-tumor immunity and response to other immune checkpoint inhibitors. Here the authors report the results of a randomized phase II trial of first-line durvalumab, paclitaxel and carboplatin with or without the anti-CD73 antibody oleclumab in patients with advanced triple-negative breast cancer.

Aberrant microRNA (miRNA) expression is associated with cancer and has potential diagnostic and prognostic value in various malignancies. In this study, we investigated miRNA profiling as a complementary tool to improve our understanding of breast cancer (BC) biology and to assess whether miRNA expression could predict clinical outcome of BC patients. Global miRNA expression profiling using microarray technology was conducted in 56 systemically untreated BC patients who had corresponding mRNA expression profiles available. Results were further confirmed using qRT-PCR in an independent dataset of 89 ER-positive BC patients homogeneously treated with tamoxifen only. MiR-210 functional analyses were performed in MCF7 and MDA-MB-231 BC cell lines using lentiviral transduction. Estrogen receptor (ER) status, tumor grade and our previously developed gene expression grade index (GGI) were associated with distinct miRNA profiles. Several miRNAs were found to be clinically relevant, including miR-210, its expression being associated with tumor proliferation and differentiation. Furthermore, miR-210 was associated with poor clinical outcome in ER-positive, tamoxifen-treated BC patients. Interestingly, the prognostic performance of miR-210 was similar to several reported multi-gene signatures, highlighting its important role in BC differentiation and tumor progression. Functional analyses in BC cell lines revealed that miR-210 is involved in cell proliferation, migration and invasion. This integrated analysis combining miRNA and mRNA expression demonstrates that miRNA expression provides additional biological information beyond mRNA expression. Expression of miR-210 is linked to tumor proliferation and appears to be a strong potential biomarker of clinical outcome in BC.

Background Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, however, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint blockade (ICB) to NACT has the potential to increase pCR rate but is hampered by the lower immunogenicity of luminal B BC. Novel strategies are needed to stimulate the immune response and increase the response rate to ICB in luminal B BC. Methods The Neo-CheckRay trial is a randomized phase II trial investigating the impact of stereotactic body radiation therapy (SBRT) to the primary breast tumor in combination with an anti-CD73 (oleclumab) to increase response to anti PD-L1 (durvalumab) and NACT. The trial is designed as a three-arm study: NACT + SBRT +/− durvalumab +/− oleclumab. The result at surgery will be evaluated using the residual cancer burden (RCB) index as the primary endpoint. Six patients will be included in a safety run-in, followed by a randomized phase II trial that will include 136 evaluable patients in 3 arms. Inclusion is limited to luminal B breast cancers that are MammaPrint genomic high risk. Discussion combination of ICB with chemotherapy in luminal B BC might benefit from immune priming agents to increase the response rate. As none have been identified so far, this phase II trial will evaluate SBRT and oleclumab as potential immune priming candidates. Trial registration trial registered on ClinicalTrials.gov ( NCT03875573 ) on March 14th, 2019.

The NeoRHEA was a single-arm phase 2 study that included patients with estrogen receptor positive / human epidermal factor receptor 2 negative early breast cancer that received 4 cycles of neoadjuvant palbociclib and endocrine therapy. The primary outcome was baseline biomarkers of treatment resistance and secondary outcome was post-treatment transcriptional and epigenetic changes of tumor, immune and stromal cells. E2F targets and G2M checkpoint proliferation-related genes gene sets were enriched in baseline samples from resistant patients., Downregulation of E2F targets and G2M checkpoint post treatment was observed in tumor, endothelial and T cells. Gene Set Enrichment Analyses (GSEA) based on genes residing in the differentially accessible peaks revealed similar effects,. Moreover, decreases in CD8 + CD103+ tissue-resident memory cell marker genes were observed post-treatment and validated by multiplex immunohistochemistry. Our data reveal that treatment with palbociclib and endocrine therapy diminishes adaptive anti-tumor immunity by decreasing T cell proliferation and the presence of tissue-resident memory T cells NCT03065621. The NeoRHEA trial showed that treatment with palbociclib and endocrine therapy decreases T cell proliferation and the presence of tissue-resident memory T cells. These results are important for the development of CDK4 selective inhibitors.

Key Points Results from trials using gene-expression assays will better define the women with oestrogen receptor-positive breast cancer and 0–3 positive axillary lymph nodes who do not need adjuvant chemotherapy Extended adjuvant hormone therapy might be an important strategy to target tumour dormancy in luminal tumours The intriguing hypothesis that bisphosphonates might decrease recurrence in women with a low-oestrogen environment is supported by subgroup analyses from several prospective trials Detecting and targeting minimal residual disease is currently being explored as a way to improve outcome for women with these tumours Targeting the PI3K/AKT/mTOR pathway is one of the most-promising approaches to reversing endocrine resistance; the intertumour and intratumour heterogeneity of luminal breast cancer has implications for designing new therapies The challenge will be to identify and target epistatic gene interactions in luminal tumours and to tailor therapy based on tumour evolution in space and time Luminal breast cancer is the most-frequently occurring subtype of breast cancer, but it is a highly heterogeneous disease. Data are emerging to assist in the stratification of patients to the optimal treatment and to address therapy resistance. This Review outlines the biology of this disease, and discusses the treatment options and ongoing studies for women with oestrogen receptor-positive breast cancer. Oestrogen receptor (ER)-positive—or luminal—tumours represent around two-thirds of all breast cancers. Luminal breast cancer is a highly heterogeneous disease comprising different histologies, gene-expression profiles and mutational patterns, with very varied clinical courses and responses to systemic treatment. Despite adjuvant endocrine therapy and chemotherapy treatment for patients at high risk of relapse, both early and late relapses still occur, a fact that highlights the unmet medical needs of these patients. Ongoing research aims to identify those patients who can be spared adjuvant chemotherapy and who will benefit from extended adjuvant hormone therapy. This research also aims to explore the role of adjuvant bisphosphonates, to interrogate new agents for targeting minimal residual disease, and to address endocrine resistance. Data from next-generation sequencing studies have given us new insight into the biology of luminal breast cancer and, together with advances in preclinical models and the availability of newer targeted agents, have led to the testing of rationally chosen combination treatments in clinical trials. However, a major challenge will be to make sense of the large amount of patient genomic data that is becoming increasingly available. This analysis will be critical to our understanding how intertumour and intratumour heterogeneity can influence treatment response and resistance.

Circulating Tumor Cells (CTCs) detection and phenotyping are currently evaluated in Breast Cancer (BC). Tumor cell dissemination has been suggested to occur early in BC progression. To interrogate dissemination in BC, we studied CTCs and HER2 expression on CTCs across the spectrum of BC staging. Spiking experiments with 6 BC cell lines were performed and blood samples from healthy women and women with BC were analyzed for HER2-positive CTCs using the CellSearch®. Based on BC cell lines experiments, HER2-positive CTCs were defined as CTCs with HER2 immunofluorescence intensity that was at least 2.5 times higher than the background. No HER2-positive CTC was detected in 42 women without BC (95% confidence interval (CI) 0-8.4%) whereas 4.1% (95%CI 1.4-11.4%) of 73 patients with ductal/lobular carcinoma in situ (DCIS/LCIS) had 1 HER2-positive CTC/22.5 mL, 7.9%, (95%CI 4.1-14.9%) of 101 women with non metastatic (M0) BC had ≥1 HER2-positive CTC/22.5 mL (median 1 cell, range 1-3 cells) and 35.9% (95%CI 22.7-51.9%) of 39 patients with metastatic BC had ≥1 HER2-positive CTC/7.5 mL (median 1.5 cells, range 1-42 cells). In CTC-positive women with DCIS/LCIS or M0 BC, HER2-positive CTCs were more commonly detected in HER2-positive (5 of 5 women) than HER2-negative BC (5 of 12 women) (p = 0.03). HER2-positive CTCs were detected in DCIS/LCIS or M0 BC irrespective of the primary tumor HER2 status. Nevertheless, their presence was more common in women with HER2-positive disease. Monitoring of HER2 expression on CTCs might be useful in trials with anti-HER2 therapies.