Cancer of unknown primary (CUP) is an enigmatic disease entity encompassing heterogeneous malignancies without a detectable primary tumour, despite a thorough diagnostic workup. A minority of ...patients with CUP (15-20%) can be assigned a putative primary tissue of origin according to clinical and histopathological findings and typically have a more favourable prognosis with the use of corresponding tumour type-specific therapies. Thus, the majority of patients with CUP have disease that cannot be assigned to a culprit primary tumour, are treated with empirical chemotherapy and have a poor prognosis. In the molecular era, the use of (epi)genomic or transcriptomic CUP classifiers and DNA or RNA sequencing offers two, sometimes overlapping, therapeutic strategies: tumour type-specific therapy and biomarker-guided therapy. Published data reveal that the accuracy of site-of-origin predictions made using CUP classifiers ranges between 54% and 98% when compared with the assignment made according to the recommended clinicopathological criteria. These advances have led to promising results in non-randomized prospective studies evaluating the efficacy of tumour type-specific therapy; however, the favourable outcomes were not confirmed in randomized controlled studies comparing this approach with standard empirical chemotherapy. Currently, the evidence supporting the use of biomarker-guided therapies is limited to case reports and small case series. In this Review, we discuss the clinical management of CUP in the era of precision medicine. We focus on the advances in understanding the biology of CUP, the implications for the diagnosis and classification of CUP according to the tissue of origin and the shift away from empirical therapy towards tailored therapy.
Cancer of unknown primary (CUP) affects a small percentage of the general population. Nonetheless, a substantial number of these patients have a poor prognosis and consequently succumb to their ...illness within a year of diagnosis. The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. This review will outline the biology of CUP by exploring the hallmarks of cancer in order to rationalise the complexities of this enigmatic syndrome. This approach will help the reader to understand where research efforts currently stand and the pitfalls of this quest.
•CUP accounts for 3–5% in the historical series.•The incidence-rate of CUP is currently decreasing and reaches 1–2%.•The reasons for the decline in the incidence-rate of CUP are speculative.•Multiple ...confounding factors should be taken into consideration in cancer-registry analysis.
Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers for which a primary tumor cannot be identified after a standardized work-up. The biology of CUP has not been fully elucidated and epidemiologic data may be helpful in this regard. The variations in the incidence-rate over time and between countries reflect changes in the risk factors for CUP, incidence trends of the primary tumors that potentially contribute to the burden of CUP and changes in the diagnostic technologies and practice. CUP accounted for 3–5% of cancers in the historical series but its incidence seems to decline in the recent publications. This paper reviews the published cancer-registry studies in order to identify and understand the variations in the incidence-rates of CUP.
The treatment landscape of metastatic renal cell carcinoma (mRCC) has been transformed with the advent of antiangiogenics, notably tyrosine kinase inhibitors (TKIs) targeting vascular endothelial ...growth factor receptor (VEGFR), and immune checkpoint inhibitors (ICIs). Both treatment options have improved outcomes of patients and modified the natural history of mRCC. Clinical investigations have focused on evaluating combination regimens containing ICIs and VEGFR-directed TKIs. Namely, the combinations of axitinib plus pembrolizumab (KEYNOTE-426) and axitinib plus avelumab (JAVELIN RENAL 101) have shown improved outcomes compared with sunitinib in treatment-naïve patients with mRCC. In this review, we discuss the clinical data of single-agent TKIs and ICIs in mRCC and the rationale for the combination ICIs and TKIs based on preclinical and clinical evidence. We also explore the current challenges for regimen selection and development of predictive biomarkers.
Opinion statement
Antibody drug-conjugates (ADCs) have revolutionized the treatment of many types of cancer, including breast cancer. Recently, two new ADCs have been approved, trastuzumab deruxtecan ...and sacituzumab govitecan; both have demonstrated impressive improvements in overall survival, trastuzumab deruxtecan in all three subtypes of metastatic breast cancer and sacituzumab govitecan in luminal and triple negative metastatic breast cancer. These drugs are the results of significant progress and innovation in the construction of the three components of an ADC, the monoclonal antibody, the payload, and the linker, and of the discovery of new target antigens. ADC engineering has profoundly changed the paradigm of cancer treatment, on one side being effective on tumors considered inherently resistant to the payload class of drugs and on the other side demonstrating activity in tumors with very low target expression. Yet, it is likely that we are just at the beginning of a new era as the identification of new targets and the introduction of new ADC constructs and combinations will expand the field of ADC rapidly over the coming years.
The identification of the HER2 alteration as an actionable oncogenic driver in breast cancer has propelled the development of HER-targeting monoclonal antibodies (mAb) such as trastuzumab and ...pertuzumab, which led to dramatic improvements in survival outcomes. Lately, the great strides made toward developing antibody-conjugation methods have led to the development of a new class of compelling compounds, the antibody-drug conjugates (ADCs) targeting HER2 which have profoundly transformed the treatment landscape of breast cancer. HER2-targeting ADCs, trastuzumab-emtansine and trastuzumab-deruxtecan, have improved the overall survival in the second and third-line settings with manageable adverse events. Other HER2-targeting ADCs using novel technological advances in the antibody, linker and/or payload conception have shown promising activity in preclinical and clinical studies and some of them are now being evaluated in larger clinical trials. Multiple challenges still impede the success of ADCs in breast cancer namely the lack of a comprehensive understanding of resistance mechanisms as well as the mechanisms of action of ADCs in special subgroups of patients such as those with low or ultra-low HER2 expression and patients with brain or leptomeningeal metastases (BM). In this framework, we review the approved indications and ongoing trials for HER2-targeting ADCs, across patient subgroups, including those with BM and discuss the associated potential mechanisms of action and resistance. Last, we provide an overview of the future perspectives involving HER2-targeting ADCs in breast cancer.
•HER2 targeting ADCs have changed the treatment landscape of metastatic HER2+ BC.•The third generation HER2 targeting ADC, T-DXd, is effective against HER2-low/ultralow BC.•The validation of new techniques to refine the definition of HER2 expression is required.•Ongoing translational research aims to evaluate the mechanisms of action and resistance to this new generation of ADC's.•Current clinical trials aim to evaluate treatment combinations and new HER2-tagreting ADCs.
DNA damage repair (DDR) defects are common in different cancer types, and these alterations can be exploited therapeutically. Epithelial ovarian cancer (EOC) is among the tumours with the highest ...percentage of hereditary cases. BRCA1 and BRCA2 predisposing pathogenic variants (PVs) were the first to be associated with EOC, whereas additional genes comprising the homologous recombination (HR) pathway have been discovered with DNA sequencing technologies. The incidence of DDR alterations among patients with metastatic prostate cancer is much higher compared to those with localized disease. Genetic testing is playing an increasingly important role in the treatment of patients with ovarian and prostate cancer. The development of poly (ADP-ribose) polymerase (PARP) inhibitors offers a therapeutic strategy for patients with EOC. One of the mechanisms of PARP inhibitors exploits the concept of synthetic lethality. Tumours with BRCA1 or BRCA2 mutations are highly sensitive to PARP inhibitors. Moreover, the synthetic lethal interaction may be exploited beyond germline BRCA mutations in the context of HR deficiency, and this is an area of ongoing research. PARP inhibitors are in advanced stages of development as a treatment for metastatic castration-resistant prostate cancer. However, there is a major concern regarding the need to identify reliable biomarkers predictive of treatment response. In this review, we explore the mechanisms of DDR, the potential for genomic analysis of ovarian and prostate cancer, and therapeutics of PARP inhibitors, along with predictive biomarkers.
Summary
Epithelial ovarian cancer (EOC) accounts for nearly 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery and neo (adjuvant) platinum-based ...chemotherapy. Relapse of advanced high grade serous ovarian cancer (HGSOC) is related to the development of drug resistance. A defective DNA damage response is a defining hallmark of HGSOC. Poly (ADP-ribose) polymerase (PARP) inhibitors exploit this deficiency through synthetic lethality and have emerged as promising anticancer therapies, especially in breast cancer gene (
BRCA1
or
BRCA2)
mutation carriers. Apart from inducing synthetic lethality, PARP inhibitors have also been shown to trap PARP1 and PARP2 on DNA, leading to PARP-DNA complexes. This “PARP trapping” potentiates synergism between PARP inhibition and both alkylating agents and platinum-based chemotherapy. However, there are remarkable differences in the ability of PARP inhibitors to trap PARP, based on the size and structure of each separate molecule. Since monotherapy with PARP inhibitors is unlikely to induce cancer cell death in
BRCA
-proficient tumors, the efficacy of PARP inhibitors could be potentially optimized when combined with DNA-damaging agents, or with molecular targeted agents that also impair mechanisms of DNA repair. Olaparib, rucaparib, and niraparib have all obtained US Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) approval in ovarian cancer in different settings. Veliparib does not yet have an approved label; nevertheless, there are currently promising results available in preclinical and early clinical settings. This comprehensive review summarizes the mechanism of action of veliparib and provides an overview of its early and ongoing clinical investigations.
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