1Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
2Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Korea
3Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
4Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
5Broad Institute of Harvard and MIT, Cambridge, MA, USA
Copyright © 2024 by the Korean Cancer Association
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Author Contributions
Conceived and designed the analysis: Kim YN, Gulhan DC, Park PJ.
Collected the data: Kim YN, Gulhan DC, Jin H, Glodzik D, Park PJ.
Contributed data or analysis tools: Jin H, Glodzik D.
Performed the analysis: Kim YN, Gulhan DC, Park PJ.
Wrote the paper: Kim YN, Gulhan DC, Jin H, Glodzik D, Park PJ.
Conflicts of Interest
Gulhan DC and Park PJ hold the patent for the SigMA algorithm.
Sequencing method |
HRD detection method |
||||
---|---|---|---|---|---|
Pros | Cons | Building blocks | Component | Example algorithms/commercial tests | |
Whole-genome sequencing (~30× germline) (~60-90× tumor; 1-5× low coverage) | Uniform and unbiased genome coverage | Low VAF variants will missed due to low coverage | SBS, ID, SV | Spectra components (BRCA1-like vs. BRCA2-like vs. HRP) | CHORD [58] |
Comprehensive identification of variants: SNVs, CNVs, SVs | Signature exposure | ||||
Purity and ploidy can be inferred | Difficulty with FFPE or low tumor purity samples | CNV | Genomic instability score (GIS), LOH+TAI+LST | HRDetect [50] | |
Accurate signature analysis | Large-scale CNVs from low (~1×) coverage sequencing | ShallowHRD [59] | |||
Panel sequencing (~50-500 genes) (~500-2,000×) | High depth allows for effective detection of SNVs in regions of interest | Variants only in prespecified regions | SBS | Signature 3 exposure (“Sig3” - HRD signature) | SigMA [57] |
CNVs are difficult to assess | CNV (> 1 Mb) | LOH (%) | Foundation Medicine (FoundationOne CDx) | ||
Data size easy to manage | Signature analysis challenging due to low mutation counts | ||||
SNP array (~3-10 kb between probes) | Robust CNV calling due to dense SNP loci coverage | No detection of somatic mutations (other than CNVs) | CNV | Genomic instability score (GIS) | Myriad (MyChoice CDx) |
CNV, copy number variation; FFPE, formalin-fixed paraffin-embedded; HRD, homologous repair deficiency; HRP, homologous repair proficient; ID, indel; LOH, loss of heterozygosity; LST, large scale translocation; SBS, single base substitution; SNP, single nucleotide polymorphism; SNV, single nucleotide variant; SV, structural variation; TAI, telomeric allelic imbalance; VAF, variant allele fraction.
Trials | Setting | Drug | HRD test | Cohort | PFS overall | PFS in HRDa) | PFS in HRP |
---|---|---|---|---|---|---|---|
Ovarian cancer: | |||||||
- Newly diagnosed setting for advanced stage, high grade: olaparib (gBRCA mutated), olaparib+bevacizumab (g/sBRCA mutated or HRD), and niraparib (any BRCA or HRD status) | |||||||
- Second-line or greater as maintenance: olaparib (any BRCA or HRD status), niraparib (gBRCA mutated), and rucaparib (g/sBRCA mutated) | |||||||
- Heavily pre-treated setting: retraction of approval | |||||||
SOLO-1 [18] | Newly diagnosed advanced | Olaparib vs. placebo | Not done | gBRCAmut (100%) | Not reached vs. 13.8 (HR 0.3, 95% CI 0.23-0.41) | NA | NA |
PAOLA-1 [67] | Newly diagnosed advanced | Olaparib+bevacizumab vs. placebo | Myriad myChoice HRD | HRD (48.0%) | 22.1 vs. 16.6 (HR 0.59, 95% CI 0.49-0.72) | 37.2 vs. 17.7 (HR 0.33, 95% CI 0.25-0.45) | 16.6 vs. 16.2 (HR 1.00, 95% CI 0.75-1.35) |
HRP (34.4%) | |||||||
Unknown (17.6%) | |||||||
PRIMA [68] | Newly diagnosed advanced | Niraparib vs. placebo | Myriad myChoice HRD | HRD (50.9%) | 13.8 vs. 8.2 (HR 0.62, 95% CI 0.5-0.76) | 21.9 vs. 10.4 (HR 0.43, 95% CI 0.31-0.59) | 8.1 vs. 5.4 (HR 0.68, 95% CI 0.49-0.94) |
HRP (49.1%) | |||||||
Study 19 [20] | Platinum-sensitive recurrent | Olaparib vs. placebo | Not done | gBRCAmut (22.8%) | 8.4 vs. 4.8 (HR 0.35, 95% CI 0.25-0.49) | NA | NA |
gBRCAwt (13.2%) | |||||||
Unknown (64.0%) | |||||||
SOLO-2 [69] | Platinum-sensitive recurrent | Olaparib vs. placebo | Not done | gBRCAmut (96.9%) | 19.1 vs. 5.5 (HR 0.3, 95% CI 0.22-0.41) | NA | NA |
Unknown (3.1%) | |||||||
NOVA [70] | Platinum-sensitive recurrent | Niraparib vs. placebo HRD | Myriad myChoice | gBRCAmut (36.7%) | Not reported | 12.9 vs. 3.8 (HR 0.38, 95% CI 0.24-0.59)b) | 6.9 vs. 3.8 (HR 0.58, 95% CI 0.36-0.92) |
gBRCAwt (63.3%) | |||||||
ARIEL3 [71] | Platinum-sensitive recurrent | Rucaparib vs. placebo | Foundation T5 NGS (s) | g/sBRCAmut (35%) | 10.8 vs. 5.4 (HR 0.36, 95% CI 0.30-0.45) | 13.6 vs. 5.4 (HR 0.44, 95% CI 0.29-0.66)c) | 6.7 vs. 5.4 (HR 0.58, 95% CI 0.4-0.85)d) |
Foundation % LOH | BRCAwt (65%) | ||||||
LOH-H (28%) | |||||||
LOH-L (29%) | |||||||
LOH-indeterminate (9%) | |||||||
Breast cancer: | |||||||
- Early stage, HER2-negative breast cancer with high risk of recurrence: olaparib (gBRCA mutated) | |||||||
- Metastatic breast cancer (HER2-negative) with prior treatment using chemotherapy in neoadjuvant, adjuvant, or metastatic setting: olaparib (gBRCA mutated) | |||||||
- Locally advanced or metastatic breast cancer (HER2-negative): talazoparib (gBRCA mutated) | |||||||
OlympiA [72] | HER2 negative, early breast cancer | Olaparib (1 year) vs. placebo | NA | gBRCAmut (100%) | 3-Year invasive disease-free survival 85.9% vs. 77.1% (HR 0.58, 95% CI 0.41-0.82) | NA | NA |
OlympiADe) [73] | HER2, negative, recurrent or metastatic | Olaparib vs. physician’s choice single-agent chemotherapy | NA | gBRCAmut (100%) | 7.0 vs. 4.2 (HR 0.58, 95% CI 0.43-0.80) | NA | NA |
EMBRACAe) [74] | Locally advanced or metastatic | Talazoparib vs. physician’s choice single-agent chemotherapy | NA | gBRCAmut (100%) | 8.6 vs. 5.6 (HR 0.54, 95% CI 0.43-0.80) | NA | NA |
Prostate cancer: | |||||||
- Metastatic castration-resistant prostate cancer (mCRPC) | |||||||
- With progression on prior treatment with enzalutamide or abiraterone: olaparib (g/s HRR gene mutated) | |||||||
- Who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy: rucaparib (g/s BRCA mutated) | |||||||
- First-line setting for mCRPC: olaparib+abiraterone+prednisone (HRR mutated) and talazoparib+enzaluta mide (BRCA mutated) | |||||||
PROfounde) [61] | mCRPC, failed prior treatment with new hormonal agent | Olaparib vs. physician’s choice single-agent chemotherapy | FoundationOne CDxf) | Cohort A: BRCA1, BRCA2, ATM (34.8%) | Cohort A: 7.4 vs. 3.6 (HR 0.34, 95% CI 0.25-0.47) | NA | NA |
Cohort B: 12 other prespecified genes (63.3%)g) | Cohort A+B: 5.8 vs. 3.5 (HR 0.49, 95% CI 0.38-0.63) | ||||||
TRITON-2e) [75] | mCRPC, failed prior treatment with hormonal agent and 1 prior taxane-based chemotherapy | Rucaparib (phase II single arm) | NA | g/s mutation in BRCA1, BRCA2, ATM, or 12 other prespecified genesh) | ORR 43.5% (31.0-56.7%), DOR not reached (6.4 months to not reached) | NA | NA |
TALAPRO-2 [76] | First-line mCRPC on androgen deprivation therapy | Talazoparib+enzalutamide vs. placebo+enzalutamide | FoundationOne CDx | HRRmut (20.7%)i) | Not reached vs. 21.9 (HR 0.63, 95% CI 0.51-0.78) | 27.9 vs. 16.4 (HR 0.46, 95% CI 0.30-0.70) | Not reached vs. 22.5 (HR 0.70, 95% CI 0.54-0.89)j) |
HRRwt (52.9%) | |||||||
Unknown (26.4%) | |||||||
PROpel [77] | First-line mCRPC with no previous systemic treatment | Olaparib+abiraterone vs. placebo+abiraterone | FoundationOne CDx | HRRmut (27.8%)k) | 24.8 vs. 16.6 (HR 0.66, 95% CI 0.54-0.81) | Not reached vs. 13.9 (HR 0.5, 95% CI 0.34-0.73) | 24.1 vs. 19.0 (HR 0.76, 95% CI 0.60-0.97) |
HRRwt (69.9%) | |||||||
Unknown (2.3%) | |||||||
Pancreatic cancer | |||||||
- Metastatic pancreatic adenocarcinoma who have not progressed on at least 16 weeks of 1st line platinum chemotherapy: olaparib (gBRCA mutated) | |||||||
POLO [78] | Metastatic, not progressed during first-line platinum-based chemotherapy | Olaparib vs. placebo | NA | gBRCAmut (100%) | 7.4 vs. 3.8 (HR 0.53, 95% CI 0.35-0.82) | NA | NA |
CI, confidence interval; DOR, duration of response; FDA, Food and Drug Administration; g, germline; g/sBRCA, germline or somatic BRCA; s, somatic; HR, hazard ratio; HRD, homologous recombination deficiency; HRP, homologous recombination proficient; HRR, homologous recombination repair gene; LOH, loss of heterozygosity; mut, mutated; NA, not available; NGS, next generation sequencing; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; wt, wildtype.
a) HRD indicates HRD (without further genomic stratification) or HRR gene mutation based on the respective HRD testing platform that was utilized,
b) PFS in HRD+gBRCA wildtype,
c) HRD defined as g/sBRCA mut or LOH-high (LOH-H),
d) PFS in g/sBRCA wildtype and LOH-low (LOH-L),
e) Note that PARP inhibitor was given as “treatment” and compared with physicians’ choice single-agent chemotherapy or hormonal therapy. This is in contrast with cases in ovarian cancer where PARP inhibitor was given as “maintenance” (i.e., immediately preceded by chemotherapy),
f) Germline vs. somatic distinction and analysis are not reported,
g) 12 genes: BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L,
h) 12 genes: BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, and RAD54L,
i) BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12,
j) HRR mutation status proficient or unknown,
k) BRCA1, BRCA2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, PANCL, RAD51B, RAD51C, RAD51D, RAD54L.
Sequencing method |
HRD detection method |
||||
---|---|---|---|---|---|
Pros | Cons | Building blocks | Component | Example algorithms/commercial tests | |
Whole-genome sequencing (~30× germline) (~60-90× tumor; 1-5× low coverage) | Uniform and unbiased genome coverage | Low VAF variants will missed due to low coverage | SBS, ID, SV | Spectra components (BRCA1-like vs. BRCA2-like vs. HRP) | CHORD [58] |
Comprehensive identification of variants: SNVs, CNVs, SVs | Signature exposure | ||||
Purity and ploidy can be inferred | Difficulty with FFPE or low tumor purity samples | CNV | Genomic instability score (GIS), LOH+TAI+LST | HRDetect [50] | |
Accurate signature analysis | Large-scale CNVs from low (~1×) coverage sequencing | ShallowHRD [59] | |||
Panel sequencing (~50-500 genes) (~500-2,000×) | High depth allows for effective detection of SNVs in regions of interest | Variants only in prespecified regions | SBS | Signature 3 exposure (“Sig3” - HRD signature) | SigMA [57] |
CNVs are difficult to assess | CNV (> 1 Mb) | LOH (%) | Foundation Medicine (FoundationOne CDx) | ||
Data size easy to manage | Signature analysis challenging due to low mutation counts | ||||
SNP array (~3-10 kb between probes) | Robust CNV calling due to dense SNP loci coverage | No detection of somatic mutations (other than CNVs) | CNV | Genomic instability score (GIS) | Myriad (MyChoice CDx) |
Trials | Setting | Drug | HRD test | Cohort | PFS overall | PFS in HRD |
PFS in HRP |
---|---|---|---|---|---|---|---|
Ovarian cancer: | |||||||
- Newly diagnosed setting for advanced stage, high grade: olaparib (gBRCA mutated), olaparib+bevacizumab (g/sBRCA mutated or HRD), and niraparib (any BRCA or HRD status) | |||||||
- Second-line or greater as maintenance: olaparib (any BRCA or HRD status), niraparib (gBRCA mutated), and rucaparib (g/sBRCA mutated) | |||||||
- Heavily pre-treated setting: retraction of approval | |||||||
SOLO-1 [18] | Newly diagnosed advanced | Olaparib vs. placebo | Not done | gBRCAmut (100%) | Not reached vs. 13.8 (HR 0.3, 95% CI 0.23-0.41) | NA | NA |
PAOLA-1 [67] | Newly diagnosed advanced | Olaparib+bevacizumab vs. placebo | Myriad myChoice HRD | HRD (48.0%) | 22.1 vs. 16.6 (HR 0.59, 95% CI 0.49-0.72) | 37.2 vs. 17.7 (HR 0.33, 95% CI 0.25-0.45) | 16.6 vs. 16.2 (HR 1.00, 95% CI 0.75-1.35) |
HRP (34.4%) | |||||||
Unknown (17.6%) | |||||||
PRIMA [68] | Newly diagnosed advanced | Niraparib vs. placebo | Myriad myChoice HRD | HRD (50.9%) | 13.8 vs. 8.2 (HR 0.62, 95% CI 0.5-0.76) | 21.9 vs. 10.4 (HR 0.43, 95% CI 0.31-0.59) | 8.1 vs. 5.4 (HR 0.68, 95% CI 0.49-0.94) |
HRP (49.1%) | |||||||
Study 19 [20] | Platinum-sensitive recurrent | Olaparib vs. placebo | Not done | gBRCAmut (22.8%) | 8.4 vs. 4.8 (HR 0.35, 95% CI 0.25-0.49) | NA | NA |
gBRCAwt (13.2%) | |||||||
Unknown (64.0%) | |||||||
SOLO-2 [69] | Platinum-sensitive recurrent | Olaparib vs. placebo | Not done | gBRCAmut (96.9%) | 19.1 vs. 5.5 (HR 0.3, 95% CI 0.22-0.41) | NA | NA |
Unknown (3.1%) | |||||||
NOVA [70] | Platinum-sensitive recurrent | Niraparib vs. placebo HRD | Myriad myChoice | gBRCAmut (36.7%) | Not reported | 12.9 vs. 3.8 (HR 0.38, 95% CI 0.24-0.59) |
6.9 vs. 3.8 (HR 0.58, 95% CI 0.36-0.92) |
gBRCAwt (63.3%) | |||||||
ARIEL3 [71] | Platinum-sensitive recurrent | Rucaparib vs. placebo | Foundation T5 NGS (s) | g/sBRCAmut (35%) | 10.8 vs. 5.4 (HR 0.36, 95% CI 0.30-0.45) | 13.6 vs. 5.4 (HR 0.44, 95% CI 0.29-0.66) |
6.7 vs. 5.4 (HR 0.58, 95% CI 0.4-0.85) |
Foundation % LOH | BRCAwt (65%) | ||||||
LOH-H (28%) | |||||||
LOH-L (29%) | |||||||
LOH-indeterminate (9%) | |||||||
Breast cancer: | |||||||
- Early stage, HER2-negative breast cancer with high risk of recurrence: olaparib (gBRCA mutated) | |||||||
- Metastatic breast cancer (HER2-negative) with prior treatment using chemotherapy in neoadjuvant, adjuvant, or metastatic setting: olaparib (gBRCA mutated) | |||||||
- Locally advanced or metastatic breast cancer (HER2-negative): talazoparib (gBRCA mutated) | |||||||
OlympiA [72] | HER2 negative, early breast cancer | Olaparib (1 year) vs. placebo | NA | gBRCAmut (100%) | 3-Year invasive disease-free survival 85.9% vs. 77.1% (HR 0.58, 95% CI 0.41-0.82) | NA | NA |
OlympiAD |
HER2, negative, recurrent or metastatic | Olaparib vs. physician’s choice single-agent chemotherapy | NA | gBRCAmut (100%) | 7.0 vs. 4.2 (HR 0.58, 95% CI 0.43-0.80) | NA | NA |
EMBRACA |
Locally advanced or metastatic | Talazoparib vs. physician’s choice single-agent chemotherapy | NA | gBRCAmut (100%) | 8.6 vs. 5.6 (HR 0.54, 95% CI 0.43-0.80) | NA | NA |
Prostate cancer: | |||||||
- Metastatic castration-resistant prostate cancer (mCRPC) | |||||||
- With progression on prior treatment with enzalutamide or abiraterone: olaparib (g/s HRR gene mutated) | |||||||
- Who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy: rucaparib (g/s BRCA mutated) | |||||||
- First-line setting for mCRPC: olaparib+abiraterone+prednisone (HRR mutated) and talazoparib+enzaluta mide (BRCA mutated) | |||||||
PROfound |
mCRPC, failed prior treatment with new hormonal agent | Olaparib vs. physician’s choice single-agent chemotherapy | FoundationOne CDx |
Cohort A: BRCA1, BRCA2, ATM (34.8%) | Cohort A: 7.4 vs. 3.6 (HR 0.34, 95% CI 0.25-0.47) | NA | NA |
Cohort B: 12 other prespecified genes (63.3%) |
Cohort A+B: 5.8 vs. 3.5 (HR 0.49, 95% CI 0.38-0.63) | ||||||
TRITON-2 |
mCRPC, failed prior treatment with hormonal agent and 1 prior taxane-based chemotherapy | Rucaparib (phase II single arm) | NA | g/s mutation in BRCA1, BRCA2, ATM, or 12 other prespecified genes |
ORR 43.5% (31.0-56.7%), DOR not reached (6.4 months to not reached) | NA | NA |
TALAPRO-2 [76] | First-line mCRPC on androgen deprivation therapy | Talazoparib+enzalutamide vs. placebo+enzalutamide | FoundationOne CDx | HRRmut (20.7%) |
Not reached vs. 21.9 (HR 0.63, 95% CI 0.51-0.78) | 27.9 vs. 16.4 (HR 0.46, 95% CI 0.30-0.70) | Not reached vs. 22.5 (HR 0.70, 95% CI 0.54-0.89) |
HRRwt (52.9%) | |||||||
Unknown (26.4%) | |||||||
PROpel [77] | First-line mCRPC with no previous systemic treatment | Olaparib+abiraterone vs. placebo+abiraterone | FoundationOne CDx | HRRmut (27.8%) |
24.8 vs. 16.6 (HR 0.66, 95% CI 0.54-0.81) | Not reached vs. 13.9 (HR 0.5, 95% CI 0.34-0.73) | 24.1 vs. 19.0 (HR 0.76, 95% CI 0.60-0.97) |
HRRwt (69.9%) | |||||||
Unknown (2.3%) | |||||||
Pancreatic cancer | |||||||
- Metastatic pancreatic adenocarcinoma who have not progressed on at least 16 weeks of 1st line platinum chemotherapy: olaparib (gBRCA mutated) | |||||||
POLO [78] | Metastatic, not progressed during first-line platinum-based chemotherapy | Olaparib vs. placebo | NA | gBRCAmut (100%) | 7.4 vs. 3.8 (HR 0.53, 95% CI 0.35-0.82) | NA | NA |
CNV, copy number variation; FFPE, formalin-fixed paraffin-embedded; HRD, homologous repair deficiency; HRP, homologous repair proficient; ID, indel; LOH, loss of heterozygosity; LST, large scale translocation; SBS, single base substitution; SNP, single nucleotide polymorphism; SNV, single nucleotide variant; SV, structural variation; TAI, telomeric allelic imbalance; VAF, variant allele fraction.
CI, confidence interval; DOR, duration of response; FDA, Food and Drug Administration; g, germline; g/sBRCA, germline or somatic BRCA; s, somatic; HR, hazard ratio; HRD, homologous recombination deficiency; HRP, homologous recombination proficient; HRR, homologous recombination repair gene; LOH, loss of heterozygosity; mut, mutated; NA, not available; NGS, next generation sequencing; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; wt, wildtype. HRD indicates HRD (without further genomic stratification) or HRR gene mutation based on the respective HRD testing platform that was utilized, PFS in HRD+gBRCA wildtype, HRD defined as g/sBRCA mut or LOH-high (LOH-H), PFS in g/sBRCA wildtype and LOH-low (LOH-L), Note that PARP inhibitor was given as “treatment” and compared with physicians’ choice single-agent chemotherapy or hormonal therapy. This is in contrast with cases in ovarian cancer where PARP inhibitor was given as “maintenance” (i.e., immediately preceded by chemotherapy), Germline vs. somatic distinction and analysis are not reported, 12 genes: 12 genes: HRR mutation status proficient or unknown,