Oligometastasis: Past, Present, Future Gutiontov, Stanley I; Pitroda, Sean P; Weichselbaum, Ralph R
International journal of radiation oncology, biology, physics,
11/2020, Letnik:
108, Številka:
3
Journal Article
Recenzirano
In this review, we discuss the oligometastatic state, with a focus on its current and future relevance within the field of radiation therapy. We first outline the scope of the problem and the ...evolving understanding of metastatic disease existing along a spectrum. We then transition to a discussion of the clinical data that led to the formulation of the oligometastatic hypothesis, delving in some detail into the clinical factors associated with improved outcomes in the setting of local therapy-whether surgical or radiotherapeutic. In particular, we highlight the marked limitations of using clinical criteria alone to determine the absence or presence of true extracranial oligometastatic disease. After this, we briefly discuss the radiation therapy literature that has recently demonstrated benefits in cancer-specific outcomes with ablative treatment of oligometastatic disease. We emphasize data in the setting of non-small cell lung cancer and prostate cancer and briefly discuss the importance of our enhanced ability to detect occult metastatic disease with improved imaging technologies. After noting that resulted and ongoing prospective trials of ablative radiation therapy use the most rudimentary of oligometastatic classifiers-number of metastases-as their inclusion criteria, we transition to our core argument: a growing body of preclinical and translational work aims to refine the definition of oligometastatic disease using molecular features. We address genomic, epigenetic, and immunologic features that have, across histology, demonstrated an improved ability to prognosticate when combined with classic clinical correlates of oligometastatic disease. We also discuss studies that suggest particular molecular targets which, when manipulated for therapeutic purposes, have the potential to revert the polymetastatic phenotype to the oligometastatic one. We conclude with what we believe are the repercussions of this work for radiation therapy trials and clinical practice, and the importance of enriching and supporting these inquiries for the future of our field.
Abstract Background The role of chemotherapy in metastatic non castrate prostate cancer (mNCPC) is debated. Survival benefits of docetaxel (D) added to androgen-deprivation therapy (ADT) were shown ...in the CHAARTED trial in patients with metastatic high-volume disease (HVD). Objective To assess the impact of metastatic burden and to update overall survival (OS) data of the GETUG-AFU15 study. Design, setting, and participants Randomized phase 3 trial of ADT plus D versus ADT alone in 385 mNCPC patients; median follow-up of 7 yr. Outcome measurements and statistical analysis Primary end point was OS. Secondary end points were biochemical progression-free survival (bPFS) and radiographic progression-free survival (rPFS). Retrospective analysis was by tumor volume. Results and limitations After a median follow-up of 83.9 mo, median OS in the overall population was 62.1 mo (95% confidence interval CI, 49.5–73.7) and 48.6 mo (95% CI, 40.9–60.6) for ADT plus D and ADT arms, respectively (hazard ratio HR: 0.88 95% CI, 0.68–1.14; p = 0.3). Median OS in ADT plus D and ADT arms, respectively, was for HVD patients: 39.8 mo (95% CI, 28.0–53.4) versus 35.1 mo (95% CI, 29.9–43.6) (HR: 0.78 95% CI, 0.56–1.09; p = 0.14), for low-volume disease (LVD) patients; median was not reached (NR; 95% CI, 69.5–NR) and 83.4 mo (95% CI, 61.8–NR) (HR: 1.02 95% CI, 0.67–1.55; p = 0.9). For upfront metastatic patients, OS was 52.6 mo (95% CI, 43.3–66.8) and 41.5 mo (95% CI, 36.3–54.5), respectively (HR: 0.93 95% CI, 0.69–1.25; p = 0.6). The bPFS (HR: 0.73 95% CI, 0.56–0.94; p = 0.014) and rPFS (HR: 0.75 95% CI, 0.58–0.97; p = 0.030) were significantly longer in the ADT plus D arm. Limitations included the retrospective analysis of metastatic extent and the lack of statistical power to detect a significant difference in subgroups. Conclusions The post hoc analyses of the GETUG-AFU15 study demonstrated a nonsignificant 20% reduction in the risk of death in the HVD subgroup. Patients with LVD had no survival improvement with early D. Patient summary In this study, docetaxel added to castration did not improve survival in patients with metastatic hormone-sensitive prostate cancer, partly due to methodological issues. However, early chemotherapy should be discussed with all patients, given the data of three randomized trials including GETUG-AFU15.
The role of epithelial-to-mesenchymal transition (EMT) in metastasis is a longstanding source of debate, largely owing to an inability to monitor transient and reversible EMT phenotypes in vivo. Here ...we establish an EMT lineage-tracing system to monitor this process in mice, using a mesenchymal-specific Cre-mediated fluorescent marker switch system in spontaneous breast-to-lung metastasis models. We show that within a predominantly epithelial primary tumour, a small proportion of tumour cells undergo EMT. Notably, lung metastases mainly consist of non-EMT tumour cells that maintain their epithelial phenotype. Inhibiting EMT by overexpressing the microRNA miR-200 does not affect lung metastasis development. However, EMT cells significantly contribute to recurrent lung metastasis formation after chemotherapy. These cells survived cyclophosphamide treatment owing to reduced proliferation, apoptotic tolerance and increased expression of chemoresistance-related genes. Overexpression of miR-200 abrogated this resistance. This study suggests the potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, for breast cancer treatment.
It is well established that organs of future metastasis are not passive receivers of circulating tumour cells, but are instead selectively and actively modified by the primary tumour before ...metastatic spread has even occurred. Sowing the 'seeds' of metastasis requires the action of tumour-secreted factors and tumour-shed extracellular vesicles that enable the 'soil' at distant metastatic sites to encourage the outgrowth of incoming cancer cells. In this Review, we summarize the main processes and new mechanisms involved in the formation of the pre-metastatic niche.
Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy
. The study of large patient cohorts incorporating longitudinal plasma ...sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study
. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.
Cancer progression is driven in part by genomic alterations
. The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations
, leading to the concept that ...generation of genomic profiling in patients with cancer could allow the selection of effective therapies
. Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment
with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT)
(adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27-0.61, P < 0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56-1.06, P = 0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76-1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2 mutations (n = 49) derived high benefit from olaparib (gBRCA1: HR = 0.36, 90% CI: 0.14-0.89; gBRCA2: HR = 0.37, 90% CI: 0.17-0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer.
The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 ...(CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer.
We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points.
Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%).
This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.).
Potassium channels are pore-forming transmembrane proteins that regulate a multitude of biological processes by controlling potassium flow across cell membranes. Aberrant potassium channel functions ...contribute to diseases such as epilepsy, cardiac arrhythmia, and neuromuscular symptoms collectively known as channelopathies. Increasing evidence suggests that cancer constitutes another category of channelopathies associated with dysregulated channel expression. Indeed, potassium channel-modulating agents have demonstrated antitumor efficacy. Potassium channels regulate cancer cell behaviors such as proliferation and migration through both canonical ion permeation-dependent and noncanonical ion permeation-independent functions. Given their cell surface localization and well-known pharmacology, pharmacological strategies to target potassium channel could prove to be promising cancer therapeutics.
Ongoing research into the application of nanotechnology for cancer treatment and diagnosis has demonstrated its advantages within contemporary oncology as well as its intrinsic limitations. The ...National Cancer Institute publishes the Cancer Nanotechnology Plan every 5 years since 2005. The most recent iteration helped codify the ongoing basic and translational efforts of the field and displayed its breadth with several evolving areas. From merely a technological perspective, this field has seen tremendous growth and success. However, an incomplete understanding of human cancer biology persists relative to the application of nanoscale materials within contemporary oncology. As such, this review presents several evolving areas in cancer nanotechnology in order to identify key clinical and biological challenges that need to be addressed to improve patient outcomes. From this clinical perspective, a sampling of the nano-enabled solutions attempting to overcome barriers faced by traditional therapeutics and diagnostics in the clinical setting are discussed. Finally, a strategic outlook of the future is discussed to highlight the need for next-generation cancer nanotechnology tools designed to address critical gaps in clinical cancer care.
Targeting metastatic cancer Ganesh, Karuna; Massagué, Joan
Nature medicine,
01/2021, Letnik:
27, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of metastasis-initiating cells that ...results in tumor growth in distant organs, evasion of immune surveillance and co-option of metastatic microenvironments. Here we review recent progress that is enabling therapeutic advances in treating both micro- and macrometastases. Such insights were gained from cancer sequencing, mechanistic studies and clinical trials, including of immunotherapy. These studies reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes.
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