With an estimated 1.4 million new cases and 375,000 deaths worldwide, prostate cancer was the second most frequent cancer and the fifth leading cause of cancer death among men in 2020 (1). Metastatic prostate cancer (mPC) is a notoriously difficult-to-treat and highly heterogeneous disease. The development of more effective and personalized treatment strategies for this patient population represents an unmet clinical need.
The recent approval of poly(ADP-ribose) polymerase – PARP inhibitors (PARPi) for the targeted treatment of prostate cancer with mutations in homologous-recombination repair (HRR) genes, together with other genomic alterations, show promise in more precisely steering treatment decisions. These developments have spurred the incorporation of tumor genomic profiling into the clinic, with present guidelines recommending molecular profiling in subsets of patients with mPC.
Despite such progress, the integration of genomic biomarkers into the clinical management of patients is limited to highly selected patient populations at a relatively small number of academic research centers.Extending the promise of personalized medicine to an increasing number of mPC patients in routine practice will require more diverse and ‘real-world’ patient data sets from larger cohorts, along with the generation and application of novel clinical genomic insights.
“In this respect, many questions surround the optimal source of tumor tissue for the selection of patients who would be most likely to benefit from therapy with PARPi, and whether tissue biopsies collected at diagnosis can reliably inform biomarker-driven decision making at late-stage disease, and following resistance to androgen-targeted and novel hormonal therapies,” says Joaquin Mateo, Principal Investigator of VHIO’s Prostate Cancer Translational Research Group, and corresponding author of this present article (2).
Co-led by Joaquin Mateo and Amado J Zurita, The University of Texas MD Anderson Cancer Center (Texas, USA), both senior authors of this study, the investigators retrospectively analyzed data from a ‘real-world’ and large cohort of more than 1,300 metastatic prostate cancer patients who had undergone tumor genomic profiling as part of routine clinical care. They hypothesized that the prevalence of BRCA2 and other HRR-gene mutations would be similar, independently of prior androgen-targeted treatment, and primary or metastatic tumor tissue specimens.
Importantly, unlike prior studies comparing the genomic landscape of primary versus metastatic prostate tumors that included patients with localized prostate cancer who had not developed disease recurrence, the researchers compared diagnostic tumor tissue from patients with untreated primary tumors with confirmed disease progression with samples from patients who had developed resistance to treatment with at least one line of standard-of-care hormonal therapy.
Clinicogenomics: the bigger picture
By integrating genomics and clinical data, the primary objective of this study was to compare the prevalence of clinically-relevant genomic biomarkers in primary and metastatic biopsies across the disease spectrum of mPC and exposure to androgen-targeting therapies. The secondary objective was to assess clinical and genomic variables associated with high genomic loss of heterozygosity (gLOH) scores.
First, results confirmed that the frequency of some genetic alterations increased with disease progression, while others remained stable. Of particular note, the investigators discovered that the prevalence of mutations in the BRCAgene and in other HRR genes remained stable during disease evolution.
“This observation is particularly relevant in stratifying metastatic prostate cancer patients for treatment with approved PARP inhibitors. Our findings suggest that diagnostic, archival tissue biopsies can be used to molecularly match these patients for PARPi therapy based on HRR gene status, regardless of subsequent lines of treatment,” observes Joaquin Mateo, who noted that the emergence of other genomic alterations over time could require rebiopsy.
“No differences were observed between the primary and metastatic samples acquired at the same time. The time of sample acquisition, as opposed to biopsy location per se, is key. This simplifies the management of these patients in clinical practice and more reliably guides treatment decision making by avoiding the biopsy of all lesions,”adds Mateo, a Clinical Investigator and Medical Oncologist of the Vall d’Hebron University Hospital’s Medical Oncology Department, directed by VHIO’s Director Josep Tabernero.
gLOH-High as a predictive biomarker
The use of PARP inhibitors for mPC with selected HRR gene mutations such as BRCA1/2 represents a prime example of molecularly guided mPC management. However, clinical outcomes of patients with different tumor HRR-associated gene mutations, and even among those with mutations in the same gene, are heterogeneous.
Refining biomarkers of HRR deficiency beyond individual gene mutations has consequently been proposed. One potential biomarker is the fraction of the genome affected by loss-of-heterozygosity (gLOH), a measure of how much of the genome is affected by irreversible loss-of-allele events, reflective of genomic instability.
“High gLOH scores associate with PARPi sensitivity in ovarian cancer, but gLOH levels are lower in prostate cancer, even in BRCA1/2 defective tumors. We therefore carried out an independent evaluation of this candidate biomarker,” says Irene Casanova, a Post-Doctoral Fellow of Joaquin Mateo’s group and a co-author of this study.
Results of this analysis show that progression on androgen-targeted therapies associates with enrichment in aberrations of various genetic pathways as well as genomic instability as gLOH scores increase, independently of BRCA1/2 mutation status.
“Considering our data, clinical trials evaluating PARPi as monotherapy or in combination should take into account the timing of biopsy acquisition and the mutational status of TP53 and RB1 tumor suppressor genes, which are the most prevalent in later stages of disease, when analyzing the predictive value of gLOH scores,” concludes Joaquin Mateo.
——
This VHIO research was funded in part by grants received from the ”la Caixa” Foundation (CaixaResearch Advanced Oncology Research Program), FERO Foundation, and Fundació Privada CELLEX.
Joaquin Mateo is supported by the CRIS Cancer Foundation (PR_TCL_2020_10), Instituto de Salud Carlos III, Fundación AECC (LABAE20019MATE), and the US Department of Defense CDMRP (PC170510P1A Impact Award). Irene Casanova-Salas has received funding from the ”la Caixa” Foundation and the European Union’s Horizon 2020 research and innovation program (LCF/BQ/PI20/11760033).
References:
The research team observed changes in head circumf...
AtCDF3 gene induced greater production of sugars a...
Un estudio con datos de los últimos 35 años, ind...
En nuestro post hablamos sobre este interesante tipo de célula del...
La revista ‘Nature Protocols’ selecciona esta técnica como “pro...
