PARP Inhibitor Biomarkers: The Key to Precision Cancer Treatment
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PARP Inhibitor Biomarkers |
PARP inhibitors have emerged as an important class of
targeted therapies for cancers with DNA repair deficiencies, most notably
BRCA-mutated breast and ovarian cancers. However, biomarkers that can predict
response to PARP inhibitors are still being refined to maximize their benefits.
Here we explore some of the most promising PARP inhibitor biomarkers and how
they may drive more personalized cancer treatment in the future.
Homologous Recombination Deficiency Scores
One of the main mechanisms of action of PARP inhibitors is exploiting cancers
that have defects in homologous recombination (HR), the high-fidelity DNA
repair pathway. Tumors with HR deficiencies are unable to properly repair DNA
double-strand breaks and are selectively killed by PARP inhibition. Several
assays have been developed to measure a tumor’s degree of HR deficiency, known
as homologous recombination deficiency (HRD) scores.
One such assay is the myChoice HRD test from Myriad Genetics, which analyzes
loss of heterozygosity, telomeric allelic imbalance, and large-scale state
transitions in a tumor’s genome to generate an HRD score. Higher HRD scores are
strongly predictive of response to PARP inhibitors, regardless of BRCA mutation
status. Other HRD scoring tests look at specific HR genes signatures. In the
future, standardized HRD scoring may allow physicians to select optimal PARP
inhibitor candidates regardless of tumor type.
Going Beyond BRCA
It has become clear that BRCA1/2 mutations, while important biomarkers, do not
tell the whole story when it comes to PARP inhibitor response. Many
BRCA-wildtype cancers still benefit from PARP inhibitors, likely owing to
alterations in other HR genes. Researchers are working to characterize a
growing list of “BRCAness” genes that may expand PARP inhibitor indications
when abnormal.
Some key BRCAness genes include ATM, ATR, FANCA, FANCM, PALB2, RAD51C/D and
CHEK2. Prospective trials are underway using multi-gene panels to identify
HR-deficient tumors most sensitive to PARP inhibitors. Characterizing the full
spectrum of biological pathways driving HR deficiency, not just single genes,
will be crucial to optimize PARP inhibitor matching.
PARP inhibitors show great potential not just as monotherapies but in
combination regimens. Many studies are exploring their use together with
chemotherapy drugs, I/O therapies like PD-1 inhibitors, and other targeted
agents. The goal is synergistic antitumor effects at lower drug doses and
broader applicability across tumor types.
One promising combination is PARP inhibitors with platinum-based chemotherapy.
Platinum agents damage DNA through crosslinking, and preclinical models show
this damage is enhanced by PARP inhibition. Ongoing trials are testing this
double attack especially in BRCA-mutated and HRD+ tumors. PARP inhibitors are
also being combined with immune checkpoint inhibitors to stimulate potent
anticancer immune responses in the HR-deficient tumor microenvironment.
Biomarkers to identify cancers most optimized for these multi-pronged
approaches will help maximize treatment benefits.
Liquid Biopsies on the Horizon
As biomarker research continues advancing, liquid biopsies analyzing
circulating tumor DNA (ctDNA) in blood samples show promise as a non-invasive
alternative to tumor biopsy. ctDNA reflects the genomic makeup of a patient’s
cancer in real time and can be repeatedly sampled through disease progression
and treatment.
Several studies demonstrate high concordance between homologous recombination
deficiency markers in ctDNA vs. tumor tissue biopsies. This indicates ctDNA may
one day be used for HRD scoring and dynamic PARP
Inhibitors Biomarkers matching as cancers evolve genomic instability
over time. Liquid biopsies could allow continuous monitoring and individualized
treatment adjustments without repeated invasive procedures – a major advantage
as combinatorial approaches become standard.
Biomarker Discovery is Ongoing
While considerable progress has been made, ongoing research is still needed to
fully characterize the predictive landscape for PARP inhibitor benefit.
Long-term biobanking of tumor samples from clinical trials will allow applying
cutting-edge genomic technologies like whole exome/genome sequencing to uncover
new predictive markers. Correlating these genomic alterations to real-world
outcomes will further precision oncology by guiding optimal PARP inhibitor
candidate selection and dosing strategies.
As the first targeted therapies for DNA repair defective cancers, PARP
inhibitors have blazed a trail. But to maximize their impact, biomarkers must
continuously evolve step-in-step with new biological insights. The quest for
predictive biomarkers will both personalize PARP inhibitor usage today and
provide valuable lessons for developing biomarkers for the next generation of
precision cancer drugs.
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