Published Ahead of Print on April 27, 2015 as 10.1200/JCO.2014.60.5501 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.60.5501
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
R
I
A
L
Challenges in the Use of DNA Repair Deficiency As a Biomarker in Breast Cancer Philip C. Schouten, Netherlands Cancer Institute, Amsterdam, the Netherlands Sabine C. Linn, Netherlands Cancer Institute, Amsterdam, and University Medical Center Utrecht, Utrecht, the Netherlands See accompanying articles doi: 10.1200/JCO.2014.57.0085 and doi: 10.1200/JCO.2014.57.6660
The development of drug-biomarker combinations holds promise for tailoring treatment for patients with cancer on the basis of the biology of the tumor exemplified by estrogen receptor expression and blockade1 and human epidermal growth factor receptor 2 targeting.2 Approximately 85% of breast cancers have a target for therapy, but triple-negative breast cancers (TNBCs) do not.3-5 Although trials have focused on identifying the most efficacious anticancer drug (regimen) for this subtype, it may be that predictive biomarkers are required to guide treatment choices because of the intrinsic heterogeneity of TNBCs.6 Molecular characterizations have demonstrated a strong association between TNBCs and BRCA1 mutations.7-9 Preclinical mechanistic insight indicated that tumor cells with a defect in BRCA1 have impaired homologous recombination (HR), the only error-free pathway of repair of interstrand crosslinks.10-13 Cells with impaired HR display sensitivity to agents that induce such lesions.13,14 In the general breast cancer population, platinum agents that cause interstrand crosslinks are not preferred over other treatment regimens. However, given the possibility that TNBCs are enriched for such a targetable HR deficiency (HRD), platinum has attracted renewed interest as has been shown in recently published articles. Furthermore, TNBCs may be enriched for BRCA1 mutations and also for a larger group of nonmutated tumors that exhibit HRD.15-17 The use of platinum in TNBCs with biomarker analyses has been investigated in the two articles that accompany this editorial.18,19 Telli et al18 neoadjuvantly treated patients with triple-negative or BRCA1/ 2-associated breast cancer with a regimen containing gemcitabine, carboplatin, and iniparib in the PrECOG 0105 trial. Overall, a pathologic complete remission rate of 36% and acceptable toxicity of the regimen were reported.18 Isakoff et al19 conducted a phase II trial with cisplatin or carboplatin in patients with metastatic TNBC (TBCRC009; Platinum for Triple-Negative Metastatic Breast Cancer and Evaluation of p63/p73 as a Biomarker of Response). The overall response rate was 25%. Both studies reproduce previous findings of efficacy of a platinum-based regimen or platinum alone in TNBC.17 However, only a subset of patients in these trials derived clinical benefit. Therefore, secondary investigations may help identify biomarkers that associate with a preferential benefit from use of a platinum regimen, which may help guide therapy decisions. Both studies report their analysis of BRCA germline mutation status as well as potential biomarkers for assessing HRD, specifically the HRD loss of Journal of Clinical Oncology, Vol 33, 2015
heterozygosity (HRD-LOH)20 score and the HRD large-scale transition (HRD-LST)21 score. Both markers evaluate so-called genomic scars as signatures of aberrations that can be observed from singlenucleotide polymorphism array– based sequencing or similar technologies and that are associated with defects in error-free repair of interstrand crosslinks.22 The HRD-LOH score counts the numbers of LOH regions larger than 15 MB but smaller than chromosome size,20 whereas the HRD-LST score counts the number of breaks between adjacent segments of at least 10 MB.21 Cutoffs were trained to best separate tumors that had a known deleterious aberration in BRCA1/2 from those that did not. In both studies, patients with a BRCA germline mutation had higher response rates than the general cohort, and the HRD scores highly correlated with BRCA1/2 germline mutations and response rates.18,19 In addition, Telli et al18 identified BRCA1 methylation in nonmutated tumors with high HRD-LOH score, which suggests that these scores identify a subgroup of patients who could benefit from therapy that targets their HRD. Unfortunately, single-arm phase II studies do not allow proper evaluation of a biomarker as a predictor of response to therapy, and they offer limited insight on how to exploit the observed association with outcome of BRCA-associated biomarkers (Fig 1). Thus, the studies by Telli et al18 and Isakoff et al19 join several other articles published over the last decade23-25 that have reported on the potential promise of BRCA-associated HRD biomarkers but did not provide definitive data on clinical utility. It has been established that the optimal biomarker trial design requires biomarker-positive and -negative patients and patients who have been treated with and without the therapy of interest to evaluate both prognostic and predictive signals.26-31 If not included in the phase II design, such a control group could be added.32 Hence, the lack of a control arm in these two new studies is indeed a major limitation of their findings. In contrast, the TNT trial (Triple Negative Breast Cancer Trial, recently reported as an abstract) was able to more appropriately evaluate the use of HRD biomarkers, at least in patients with advanced disease.33 In that trial, patients with locally advanced or metastatic TNBC were randomly assigned to therapy with carboplatin at area under the [concentration-time] curve 6 or standard-of-care docetaxel. Of great interest, among the 376 patients in that study, 29 were known to be BRCA1 or BRCA2 mutation carriers (including 13 who had estrogen receptor–positive, HER2-negative disease). Prespecified analyses specifically addressed populations that were assumed to have © 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Univ. of Alabama at Birmingham/ LISTER HILL LIBRARY Copyright © 2015 American Society on of Clinical rights reserved. OF THE HEALTH SCIENCES July 22,Oncology. 2015 fromAll 138.26.31.3
Copyright 2015 by American Society of Clinical Oncology
1
Editorial
A
Biomarker negative
Biomarker positive Treatment of interest Other treatment
Survival
Survival
Treatment of interest Other treatment
? ?
? ?
?
? ? ?
? ?
?
?
Time Biomarker negative Treatment Other
Interest
Poor
?
% or No. of patients
Good
?
% or No. of patients
Biomarker positive Treatment Other
Interest
Poor
?
% or No. of patients
Good
?
% or No. of patients
Response
Response
B
Time
Fig 1. The necessity of control groups to assess prognostic and/or predictive value in biomarker investigations. (A) Hypothetical survival analysis of a biomarker of interest. Kaplan-Meier curves of biomarker-negative (left) and -positive (right) patients, with therapy of interest (blue) and a control treatment (gold). (B) Response analysis of a biomarker. Hypothetical cross tables of treatment versus response for biomarker-negative and -positive patients with therapy of interest (blue) and a control treatment (gold). Question marks indicate the missing information from single-drug (regimen) trials.
underlying impaired DNA repair, such as those with germline mutations in BRCA1 or BRCA2 and those whose tumors had a basal-like phenotype on the basis of immunohistochemistry or intrinsic subtyping by using the PAM50 assay. In the primary end point analysis of the TNT trial, there was no improvement in overall response favoring carboplatin over docetaxel. However, the 43 patients ultimately found to carry a germline BRCA1 or BRCA2 mutation had a much higher response rate and longer progression-free survival if treated with carboplatin (68% v 30%, respectively). At the same time, the composite score of three tests for evidence of genomic scar (HRD-LOH, HRD-LST and HRD telomeric allelic imbalance34) was not predictive for benefit of carboplatin over docetaxel. Hence, at least based on the TNT trial in patients with advanced disease,33 the ability of assays to recognize targetable HRD beyond that occurring in patients with germline BRCA1 or BRCA2 mutations remains an assumption, without high-level proof of primary sensitivity or acquired resistance in that trial or other studies.33 Although the TNT results are at odds with the results of Telli et al and Isakoff et al, the potential role of these genomic scar assays in earlier stages of disease needs further testing.20,21,34,35 Other reversible causes of BRCA1 or BRCA2 suppression, such as epigenetic changes as a result of hypermethylation, might play a bigger or smaller role in early or advanced disease. Consequently, both our enthusiasm and caution 2
© 2015 by American Society of Clinical Oncology
must be tempered while we wait for properly designed studies in the (neo)adjuvant setting. In North America, an upcoming National Clinical Trial Network randomized trial (ECOG-ACRIN 1131) will test the survival benefit of additional platinum-based chemotherapy versus observation in patients with residual triple-negative basal-like breast cancer after neoadjuvant chemotherapy. In the meantime, properly designed prospective and/or retrospective studies26,27 should continue to expand on the initial evidence of clinical benefit from the pairing of a DNA repair deficiency biomarker and a drug. Prospective and retrospective data thus far include the initial results of evaluating BRCA germline mutation status and carboplatin in metastatic disease (the TNT trial),33 BRCA1-like DNA copy number signature with platinum/veliparib in the neoadjuvant setting,36 and high-dose alkylating chemotherapy in the adjuvant setting.32,37,38 The HRD assays reported in these two studies now join several other assays that will help discover how best to incorporate markers of DNA repair impairment as part of our therapeutic tools across various tumor phenotypes and not just in TNBCs. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org. AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Univ. of Alabama at Birmingham/ LISTER HILL LIBRARY Copyright © 2015 American Society on of Clinical rights reserved. OF THE HEALTH SCIENCES July 22,Oncology. 2015 fromAll 138.26.31.3
Editorial
REFERENCES 1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005 2. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 3. Bauer KR, Brown M, Cress RD, et al: Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: A populationbased study from the California Cancer Registry. Cancer 109:1721-1728, 2007 4. Linn SC, Van’t Veer LJ: Clinical relevance of the triple-negative breast cancer concept: Genetic basis and clinical utility of the concept. Eur J Cancer 45:11-26, 2009 5. Hudis CA, Gianni L: Triple-negative breast cancer: An unmet medical need. Oncologist 16:1-11, 2011 6. Abramson VG, Lehmann BD, Ballinger TJ, et al: Subtyping of triplenegative breast cancer: Implications for therapy. Cancer 121:8-16, 2015 7. Turner N, Tutt A, Ashworth A: Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4:814-819, 2004 8. Anders C, Carey LA: Understanding and treating triple-negative breast cancer. Oncology (Williston Park) 22:1233-1239, 2008; discussion 1239-1240, 1243 9. Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 490:61-70, 2012 10. Moynahan ME, Chiu JW, Koller BH, et al: Brca1 controls homologydirected DNA repair. Mol Cell 4:511-518, 1999 11. Venkitaraman AR: Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu Rev Pathol 4:461-487, 2009 12. Ciccia A, Elledge SJ: The DNA damage response: Making it safe to play with knives. Mol Cell 40:179-204, 2010 13. Deans AJ, West SC: DNA interstrand crosslink repair and cancer. Nat Rev Cancer 11:467-480, 2011 14. Helleday T: Homologous recombination in cancer development, treatment and development of drug resistance. Carcinogenesis 31:955-960, 2010 15. Von Minckwitz G, Schneeweiss A, Loibl S, et al: Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): A randomised phase 2 trial. Lancet Oncol 15:747-756, 2014 16. Sikov WM, Berry DA, Perou CM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dosedense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33:13-21, 2015 17. Sparano JA: Defining a role and predicting benefit from platinum-based therapy in breast cancer: An evolving story. J Clin Oncol 33:1-3, 2015 18. Telli ML, Jensen KC, Vinayak S, et al: Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumor-based measure of genomic instability: PrECOG 0105. J Clin Oncol doi: 10.1200/JCO.2014.57. 0085 19. Isakoff SJ, Mayer EL, He L, et al: TBCRC009: A multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triplenegative breast cancer. J Clin Oncol doi: 10.1200/JCO.2014.57.6660 20. Abkevich V, Timms KM, Hennessy BT, et al: Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 107:1776-1782, 2012
21. Popova T, Manié E, Rieunier G, et al: Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 72:5454-5462, 2012 22. Watkins JA, Irshad S, Grigoriadis A, et al: Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res 16:211, 2014 23. Bayraktar S, Glück S: Systemic therapy options in BRCA mutationassociated breast cancer. Breast Cancer Res Treat 135:355-366, 2012 24. Imyanitov EN, Moiseyenko VM: Drug therapy for hereditary cancers. Hered Cancer Clin Pract 9:5, 2011 25. Francken AB, Schouten PC, Bleiker EM, et al: Breast cancer in women at high risk: The role of rapid genetic testing for BRCA1 and -2 mutations and the consequences for treatment strategies. Breast 22:561-568, 2013 26. Simon RM, Paik S, Hayes DF: Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 101:1446-1452, 2009 27. Henry NL, Hayes DF: Uses and abuses of tumor markers in the diagnosis, monitoring, and treatment of primary and metastatic breast cancer. Oncologist 11:541-552, 2006 28. Sargent DJ, Conley BA, Allegra C, et al: Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol 23:2020-2027, 2005 29. Mandrekar SJ, Sargent DJ: Clinical trial designs for predictive biomarker validation: One size does not fit all. J Biopharm Stat 19:530-542, 2009 30. McShane LM, Altman DG, Sauerbrei W, et al: REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229-235, 2006 31. Altman DG, McShane LM, Sauerbrei W, et al: Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): Explanation and elaboration. PLoS Med 9:e1001216, 2012 32. Schouten PC, Marmé F, Aulmann S, et al: Breast cancers with a BRCA1like DNA copy number profile recur less often than expected after high-dose alkylating chemotherapy. Clin Cancer Res 21:763-770, 2015 33. Tutt A, Ellis P, Kilburn L, et al: TNT: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/ 012). 37th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2014 (abstr S3-01) 34. Birkbak NJ, Wang ZC, Kim JY, et al: Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov 2:366-375, 2012 35. Timms KM, Abkevich V, Hughes E, et al: Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res 16:475, 2014 36. Glas A, Peeters J, Yau C, et al: Evaluation of a BRCAness signature as a predictive biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 TRIAL. Eur J Cancer 50:173, 2014 37. Vollebergh MA, Lips EH, Nederlof PM, et al: An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients. Ann Oncol 22:15611570, 2011 38. Schouten PC, Gluz O, Harbeck N, et al: BRCA1-like copy number profiles to predict benefit of high-dose alkylating chemotherapy in high-risk breast cancer (BC): Results from randomized WSG AM-01 trial. J Clin Oncol 32, 2014 (suppl 5s; abstr 11018)
DOI: 10.1200/JCO.2014.60.5501; published online ahead of print at www.jco.org on April 27, 2015
■ ■ ■
www.jco.org
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Univ. of Alabama at Birmingham/ LISTER HILL LIBRARY Copyright © 2015 American Society on of Clinical rights reserved. OF THE HEALTH SCIENCES July 22,Oncology. 2015 fromAll 138.26.31.3
3
Editorial
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Challenges in the Use of DNA Repair Deficiency As a Biomarker in Breast Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Philip C. Schouten No relationship to disclose Sabine C. Linn Consulting or Advisory Role: Roche, Sanofi, Cergentis, Novartis Research Funding: Amgen, AstraZeneca, Roche, Sanofi, Genentech Patents, Royalties, Other Intellectual Property: Named inventor on a patent application for the BRCA1-like classifier Travel, Accommodations, Expenses: Roche
© 2015 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Univ. of Alabama at Birmingham/ LISTER HILL LIBRARY Copyright © 2015 American Society on of Clinical rights reserved. OF THE HEALTH SCIENCES July 22,Oncology. 2015 fromAll 138.26.31.3
Editorial
Acknowledgment We acknowledge Tesa Severson for critically reading the manuscript and the editors of Journal of Clinical Oncology for their thoughtful input.
www.jco.org
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Univ. of Alabama at Birmingham/ LISTER HILL LIBRARY Copyright © 2015 American Society on of Clinical rights reserved. OF THE HEALTH SCIENCES July 22,Oncology. 2015 fromAll 138.26.31.3
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
R
I
A
L
Challenges in the Use of DNA Repair Deficiency As a Biomarker in Breast Cancer Philip C. Schouten, Netherlands Cancer Institute, Amsterdam, the Netherlands Sabine C. Linn, Netherlands Cancer Institute, Amsterdam, and University Medical Center Utrecht, Utrecht, the Netherlands See accompanying articles doi: 10.1200/JCO.2014.57.0085 and doi: 10.1200/JCO.2014.57.6660
The development of drug-biomarker combinations holds promise for tailoring treatment for patients with cancer on the basis of the biology of the tumor exemplified by estrogen receptor expression and blockade1 and human epidermal growth factor receptor 2 targeting.2 Approximately 85% of breast cancers have a target for therapy, but triple-negative breast cancers (TNBCs) do not.3-5 Although trials have focused on identifying the most efficacious anticancer drug (regimen) for this subtype, it may be that predictive biomarkers are required to guide treatment choices because of the intrinsic heterogeneity of TNBCs.6 Molecular characterizations have demonstrated a strong association between TNBCs and BRCA1 mutations.7-9 Preclinical mechanistic insight indicated that tumor cells with a defect in BRCA1 have impaired homologous recombination (HR), the only error-free pathway of repair of interstrand crosslinks.10-13 Cells with impaired HR display sensitivity to agents that induce such lesions.13,14 In the general breast cancer population, platinum agents that cause interstrand crosslinks are not preferred over other treatment regimens. However, given the possibility that TNBCs are enriched for such a targetable HR deficiency (HRD), platinum has attracted renewed interest as has been shown in recently published articles. Furthermore, TNBCs may be enriched for BRCA1 mutations and also for a larger group of nonmutated tumors that exhibit HRD.15-17 The use of platinum in TNBCs with biomarker analyses has been investigated in the two articles that accompany this editorial.18,19 Telli et al18 neoadjuvantly treated patients with triple-negative or BRCA1/ 2-associated breast cancer with a regimen containing gemcitabine, carboplatin, and iniparib in the PrECOG 0105 trial. Overall, a pathologic complete remission rate of 36% and acceptable toxicity of the regimen were reported.18 Isakoff et al19 conducted a phase II trial with cisplatin or carboplatin in patients with metastatic TNBC (TBCRC009; Platinum for Triple-Negative Metastatic Breast Cancer and Evaluation of p63/p73 as a Biomarker of Response). The overall response rate was 25%. Both studies reproduce previous findings of efficacy of a platinum-based regimen or platinum alone in TNBC.17 However, only a subset of patients in these trials derived clinical benefit. Therefore, secondary investigations may help identify biomarkers that associate with a preferential benefit from use of a platinum regimen, which may help guide therapy decisions. Both studies report their analysis of BRCA germline mutation status as well as potential biomarkers for assessing HRD, specifically the HRD loss of Journal of Clinical Oncology, Vol 33, 2015
heterozygosity (HRD-LOH)20 score and the HRD large-scale transition (HRD-LST)21 score. Both markers evaluate so-called genomic scars as signatures of aberrations that can be observed from singlenucleotide polymorphism array– based sequencing or similar technologies and that are associated with defects in error-free repair of interstrand crosslinks.22 The HRD-LOH score counts the numbers of LOH regions larger than 15 MB but smaller than chromosome size,20 whereas the HRD-LST score counts the number of breaks between adjacent segments of at least 10 MB.21 Cutoffs were trained to best separate tumors that had a known deleterious aberration in BRCA1/2 from those that did not. In both studies, patients with a BRCA germline mutation had higher response rates than the general cohort, and the HRD scores highly correlated with BRCA1/2 germline mutations and response rates.18,19 In addition, Telli et al18 identified BRCA1 methylation in nonmutated tumors with high HRD-LOH score, which suggests that these scores identify a subgroup of patients who could benefit from therapy that targets their HRD. Unfortunately, single-arm phase II studies do not allow proper evaluation of a biomarker as a predictor of response to therapy, and they offer limited insight on how to exploit the observed association with outcome of BRCA-associated biomarkers (Fig 1). Thus, the studies by Telli et al18 and Isakoff et al19 join several other articles published over the last decade23-25 that have reported on the potential promise of BRCA-associated HRD biomarkers but did not provide definitive data on clinical utility. It has been established that the optimal biomarker trial design requires biomarker-positive and -negative patients and patients who have been treated with and without the therapy of interest to evaluate both prognostic and predictive signals.26-31 If not included in the phase II design, such a control group could be added.32 Hence, the lack of a control arm in these two new studies is indeed a major limitation of their findings. In contrast, the TNT trial (Triple Negative Breast Cancer Trial, recently reported as an abstract) was able to more appropriately evaluate the use of HRD biomarkers, at least in patients with advanced disease.33 In that trial, patients with locally advanced or metastatic TNBC were randomly assigned to therapy with carboplatin at area under the [concentration-time] curve 6 or standard-of-care docetaxel. Of great interest, among the 376 patients in that study, 29 were known to be BRCA1 or BRCA2 mutation carriers (including 13 who had estrogen receptor–positive, HER2-negative disease). Prespecified analyses specifically addressed populations that were assumed to have © 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Univ. of Alabama at Birmingham/ LISTER HILL LIBRARY Copyright © 2015 American Society on of Clinical rights reserved. OF THE HEALTH SCIENCES July 22,Oncology. 2015 fromAll 138.26.31.3
Copyright 2015 by American Society of Clinical Oncology
1
Editorial
A
Biomarker negative
Biomarker positive Treatment of interest Other treatment
Survival
Survival
Treatment of interest Other treatment
? ?
? ?
?
? ? ?
? ?
?
?
Time Biomarker negative Treatment Other
Interest
Poor
?
% or No. of patients
Good
?
% or No. of patients
Biomarker positive Treatment Other
Interest
Poor
?
% or No. of patients
Good
?
% or No. of patients
Response
Response
B
Time
Fig 1. The necessity of control groups to assess prognostic and/or predictive value in biomarker investigations. (A) Hypothetical survival analysis of a biomarker of interest. Kaplan-Meier curves of biomarker-negative (left) and -positive (right) patients, with therapy of interest (blue) and a control treatment (gold). (B) Response analysis of a biomarker. Hypothetical cross tables of treatment versus response for biomarker-negative and -positive patients with therapy of interest (blue) and a control treatment (gold). Question marks indicate the missing information from single-drug (regimen) trials.
underlying impaired DNA repair, such as those with germline mutations in BRCA1 or BRCA2 and those whose tumors had a basal-like phenotype on the basis of immunohistochemistry or intrinsic subtyping by using the PAM50 assay. In the primary end point analysis of the TNT trial, there was no improvement in overall response favoring carboplatin over docetaxel. However, the 43 patients ultimately found to carry a germline BRCA1 or BRCA2 mutation had a much higher response rate and longer progression-free survival if treated with carboplatin (68% v 30%, respectively). At the same time, the composite score of three tests for evidence of genomic scar (HRD-LOH, HRD-LST and HRD telomeric allelic imbalance34) was not predictive for benefit of carboplatin over docetaxel. Hence, at least based on the TNT trial in patients with advanced disease,33 the ability of assays to recognize targetable HRD beyond that occurring in patients with germline BRCA1 or BRCA2 mutations remains an assumption, without high-level proof of primary sensitivity or acquired resistance in that trial or other studies.33 Although the TNT results are at odds with the results of Telli et al and Isakoff et al, the potential role of these genomic scar assays in earlier stages of disease needs further testing.20,21,34,35 Other reversible causes of BRCA1 or BRCA2 suppression, such as epigenetic changes as a result of hypermethylation, might play a bigger or smaller role in early or advanced disease. Consequently, both our enthusiasm and caution 2
© 2015 by American Society of Clinical Oncology
must be tempered while we wait for properly designed studies in the (neo)adjuvant setting. In North America, an upcoming National Clinical Trial Network randomized trial (ECOG-ACRIN 1131) will test the survival benefit of additional platinum-based chemotherapy versus observation in patients with residual triple-negative basal-like breast cancer after neoadjuvant chemotherapy. In the meantime, properly designed prospective and/or retrospective studies26,27 should continue to expand on the initial evidence of clinical benefit from the pairing of a DNA repair deficiency biomarker and a drug. Prospective and retrospective data thus far include the initial results of evaluating BRCA germline mutation status and carboplatin in metastatic disease (the TNT trial),33 BRCA1-like DNA copy number signature with platinum/veliparib in the neoadjuvant setting,36 and high-dose alkylating chemotherapy in the adjuvant setting.32,37,38 The HRD assays reported in these two studies now join several other assays that will help discover how best to incorporate markers of DNA repair impairment as part of our therapeutic tools across various tumor phenotypes and not just in TNBCs. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org. AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Univ. of Alabama at Birmingham/ LISTER HILL LIBRARY Copyright © 2015 American Society on of Clinical rights reserved. OF THE HEALTH SCIENCES July 22,Oncology. 2015 fromAll 138.26.31.3
Editorial
REFERENCES 1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005 2. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 3. Bauer KR, Brown M, Cress RD, et al: Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: A populationbased study from the California Cancer Registry. Cancer 109:1721-1728, 2007 4. Linn SC, Van’t Veer LJ: Clinical relevance of the triple-negative breast cancer concept: Genetic basis and clinical utility of the concept. Eur J Cancer 45:11-26, 2009 5. Hudis CA, Gianni L: Triple-negative breast cancer: An unmet medical need. Oncologist 16:1-11, 2011 6. Abramson VG, Lehmann BD, Ballinger TJ, et al: Subtyping of triplenegative breast cancer: Implications for therapy. Cancer 121:8-16, 2015 7. Turner N, Tutt A, Ashworth A: Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4:814-819, 2004 8. Anders C, Carey LA: Understanding and treating triple-negative breast cancer. Oncology (Williston Park) 22:1233-1239, 2008; discussion 1239-1240, 1243 9. Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 490:61-70, 2012 10. Moynahan ME, Chiu JW, Koller BH, et al: Brca1 controls homologydirected DNA repair. Mol Cell 4:511-518, 1999 11. Venkitaraman AR: Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu Rev Pathol 4:461-487, 2009 12. Ciccia A, Elledge SJ: The DNA damage response: Making it safe to play with knives. Mol Cell 40:179-204, 2010 13. Deans AJ, West SC: DNA interstrand crosslink repair and cancer. Nat Rev Cancer 11:467-480, 2011 14. Helleday T: Homologous recombination in cancer development, treatment and development of drug resistance. Carcinogenesis 31:955-960, 2010 15. Von Minckwitz G, Schneeweiss A, Loibl S, et al: Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): A randomised phase 2 trial. Lancet Oncol 15:747-756, 2014 16. Sikov WM, Berry DA, Perou CM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dosedense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33:13-21, 2015 17. Sparano JA: Defining a role and predicting benefit from platinum-based therapy in breast cancer: An evolving story. J Clin Oncol 33:1-3, 2015 18. Telli ML, Jensen KC, Vinayak S, et al: Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumor-based measure of genomic instability: PrECOG 0105. J Clin Oncol doi: 10.1200/JCO.2014.57. 0085 19. Isakoff SJ, Mayer EL, He L, et al: TBCRC009: A multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triplenegative breast cancer. J Clin Oncol doi: 10.1200/JCO.2014.57.6660 20. Abkevich V, Timms KM, Hennessy BT, et al: Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 107:1776-1782, 2012
21. Popova T, Manié E, Rieunier G, et al: Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 72:5454-5462, 2012 22. Watkins JA, Irshad S, Grigoriadis A, et al: Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res 16:211, 2014 23. Bayraktar S, Glück S: Systemic therapy options in BRCA mutationassociated breast cancer. Breast Cancer Res Treat 135:355-366, 2012 24. Imyanitov EN, Moiseyenko VM: Drug therapy for hereditary cancers. Hered Cancer Clin Pract 9:5, 2011 25. Francken AB, Schouten PC, Bleiker EM, et al: Breast cancer in women at high risk: The role of rapid genetic testing for BRCA1 and -2 mutations and the consequences for treatment strategies. Breast 22:561-568, 2013 26. Simon RM, Paik S, Hayes DF: Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 101:1446-1452, 2009 27. Henry NL, Hayes DF: Uses and abuses of tumor markers in the diagnosis, monitoring, and treatment of primary and metastatic breast cancer. Oncologist 11:541-552, 2006 28. Sargent DJ, Conley BA, Allegra C, et al: Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol 23:2020-2027, 2005 29. Mandrekar SJ, Sargent DJ: Clinical trial designs for predictive biomarker validation: One size does not fit all. J Biopharm Stat 19:530-542, 2009 30. McShane LM, Altman DG, Sauerbrei W, et al: REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229-235, 2006 31. Altman DG, McShane LM, Sauerbrei W, et al: Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): Explanation and elaboration. PLoS Med 9:e1001216, 2012 32. Schouten PC, Marmé F, Aulmann S, et al: Breast cancers with a BRCA1like DNA copy number profile recur less often than expected after high-dose alkylating chemotherapy. Clin Cancer Res 21:763-770, 2015 33. Tutt A, Ellis P, Kilburn L, et al: TNT: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/ 012). 37th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2014 (abstr S3-01) 34. Birkbak NJ, Wang ZC, Kim JY, et al: Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov 2:366-375, 2012 35. Timms KM, Abkevich V, Hughes E, et al: Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res 16:475, 2014 36. Glas A, Peeters J, Yau C, et al: Evaluation of a BRCAness signature as a predictive biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 TRIAL. Eur J Cancer 50:173, 2014 37. Vollebergh MA, Lips EH, Nederlof PM, et al: An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients. Ann Oncol 22:15611570, 2011 38. Schouten PC, Gluz O, Harbeck N, et al: BRCA1-like copy number profiles to predict benefit of high-dose alkylating chemotherapy in high-risk breast cancer (BC): Results from randomized WSG AM-01 trial. J Clin Oncol 32, 2014 (suppl 5s; abstr 11018)
DOI: 10.1200/JCO.2014.60.5501; published online ahead of print at www.jco.org on April 27, 2015
■ ■ ■
www.jco.org
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Univ. of Alabama at Birmingham/ LISTER HILL LIBRARY Copyright © 2015 American Society on of Clinical rights reserved. OF THE HEALTH SCIENCES July 22,Oncology. 2015 fromAll 138.26.31.3
3
Editorial
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Challenges in the Use of DNA Repair Deficiency As a Biomarker in Breast Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Philip C. Schouten No relationship to disclose Sabine C. Linn Consulting or Advisory Role: Roche, Sanofi, Cergentis, Novartis Research Funding: Amgen, AstraZeneca, Roche, Sanofi, Genentech Patents, Royalties, Other Intellectual Property: Named inventor on a patent application for the BRCA1-like classifier Travel, Accommodations, Expenses: Roche
© 2015 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Univ. of Alabama at Birmingham/ LISTER HILL LIBRARY Copyright © 2015 American Society on of Clinical rights reserved. OF THE HEALTH SCIENCES July 22,Oncology. 2015 fromAll 138.26.31.3
Editorial
Acknowledgment We acknowledge Tesa Severson for critically reading the manuscript and the editors of Journal of Clinical Oncology for their thoughtful input.
www.jco.org
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Univ. of Alabama at Birmingham/ LISTER HILL LIBRARY Copyright © 2015 American Society on of Clinical rights reserved. OF THE HEALTH SCIENCES July 22,Oncology. 2015 fromAll 138.26.31.3
