VOLUME
34
•
NUMBER
6
•
FEBRUARY
20,
2016
JOURNAL OF CLINICAL ONCOLOGY
C O R R E S P O N D E N C E
Reply to A. Oguz et al
Eileen Holmes, Christine Campbell, and Ian Bradbury
We appreciate the interest of Oguz et al1 in our meta-analysis of five large adjuvant trials to compare the efficacy of chemotherapy and trastuzumab versus chemotherapy alone in patients with small human epidermal growth factor 2 (HER2)–positive breast cancers of 2 cm or smaller.2 Their questions are important, because they relate to the potential to reduce the intensity of standard treatment of patients with small HER2-positive breast cancers. We agree that there are limited prospective data about the prognosis of T1abN0 HER2-positive tumors. Few of these patients were included in the randomized adjuvant trastuzumab trials because of concerns about potential cardiotoxicity with trastuzumab in patients perceived to be at low risk of recurrence. Therefore, we cannot provide additional prognostic information for patients with T1abN0 HER2-positive breast cancers. Such information must be obtained from retrospective series3-7 or prospective cohort studies.8,9 In addition, the selection of chemotherapy regimens for patients with small HER2-positive tumors is important, and we observed heterogeneous outcomes among the trials for the hormone receptor (HR)–negative cohort, which may be due in part to the difference in timing of chemotherapy. Thus, we hesitate to make any additional conclusions, because patients were not randomly assigned to chemotherapy regimens. Finally, we agree that additional analyses of retrospective series and prospective cohort studies will be important to identify additional patient subgroups that may warrant less (or more) intensive treatments. For example, in a previous meta-analysis of five of the adjuvant randomized trastuzumab trials, we identified a subgroup of patients with HR-positive, HER2-positive tumors of 2 cm or smaller, and one or no positive lymph nodes, who had excellent prognoses when treated with trastuzumab and chemotherapy with or without endocrine therapy; the 5-year disease-free survival was 91%, and the 5-year overall survival was 97%.10 These results, we hope, will provide a benchmark for the design of future trials to evaluate less aggressive treatment approaches.
Jo Anne Zujewski
Ciara C. O’Sullivan National Cancer Institute, National Institutes of Health, Bethesda, MD
Frontier Science, Inverness-shire, Scotland
National Cancer Institute, National Institutes of Health, Bethesda, MD
Richard D. Gelber Harvard Medical School, Harvard T.H. Chan School of Public Health, Dana-Farber Cancer Institute, and Frontier Science and Technology Research Foundation, Boston, MA
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org REFERENCES 1. Oguz A, Keskin GS, Colak D, et al: Treatment of lymph node–negative, earlystage HER2-positive breast cancer. J Clin Oncol 34:639-640, 2016 2. O’Sullivan CC, Bradbury I, Campbell C, et al: Efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2-positive early breast cancer and tumors # 2 cm: A meta-analysis of the randomized trastuzumab trials. J Clin Oncol 33:2600-2608, 2015 ´ 3. Rodrigues MJ, Peron J, Frenel JS, et al: Benefit of adjuvant trastuzumabbased chemotherapy in T1ab node-negative HER2-overexpressing breast carcinomas: A multicenter retrospective series. Ann Oncol 24:916-924, 2013 4. Chia S, Norris B, Speers C, et al: Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of nodenegative breast cancers. J Clin Oncol 26:5697-5704, 2008 5. Curigliano G, Viale G, Bagnardi V, et al: Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer. J Clin Oncol 27:5693-5699, 2009 6. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al: High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2positive, node-negative tumors 1 cm or smaller. J Clin Oncol 27:5700-5706, 2009 7. Fehrenbacher L, Capra AM, Quesenberry CP Jr. et al: Distant invasive breast cancer recurrence risk in human epidermal growth factor receptor 2-positive T1a and T1b node-negative localized breast cancer diagnosed from 2000 to 2006: A cohort from an integrated health care delivery system. J Clin Oncol 32:2151-2158, 2014 8. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015 9. Vaz-Luis I, Ottesen RA, Hughes ME, et al: Outcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: A multiinstitutional study. J Clin Oncol 32:2142-2150, 2014 10. O’Sullivan CC, Holmes E, Spielmann M, et al: The prognosis of small HER2positive breast cancers: A meta-analysis of the randomized trastuzumab trials. Presented at the 36th CTRC-AACR San Antonio Breast Cancer Symposium, San Antonio, TX, December 10-14, 2013
DOI: 10.1200/JCO.2015.65.1034; published online ahead of print at www.jco.org on December 7, 2015
n n n
640
© 2015 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 34, No 6 (February 20), 2016: pp 640
Downloaded from jco.ascopubs.org on June 21, 2016. For personal use only. No other uses without permission. Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
Correspondence
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Reply to A. Oguz et al. The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 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. Ciara C. O’Sullivan No relationship to disclose
Jo Anne Zujewski No relationship to disclose
Eileen Holmes No relationship to disclose
Richard D. Gelber Research Funding: AstraZeneca (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Roche (Inst), Celgene (Inst), Merck (Inst), Pfizer (Inst)
Christine Campbell No relationship to disclose Ian Bradbury No relationship to disclose
www.jco.org
© 2015 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on June 21, 2016. For personal use only. No other uses without permission. Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
34
•
NUMBER
6
•
FEBRUARY
20,
2016
JOURNAL OF CLINICAL ONCOLOGY
C O R R E S P O N D E N C E
Reply to A. Oguz et al
Eileen Holmes, Christine Campbell, and Ian Bradbury
We appreciate the interest of Oguz et al1 in our meta-analysis of five large adjuvant trials to compare the efficacy of chemotherapy and trastuzumab versus chemotherapy alone in patients with small human epidermal growth factor 2 (HER2)–positive breast cancers of 2 cm or smaller.2 Their questions are important, because they relate to the potential to reduce the intensity of standard treatment of patients with small HER2-positive breast cancers. We agree that there are limited prospective data about the prognosis of T1abN0 HER2-positive tumors. Few of these patients were included in the randomized adjuvant trastuzumab trials because of concerns about potential cardiotoxicity with trastuzumab in patients perceived to be at low risk of recurrence. Therefore, we cannot provide additional prognostic information for patients with T1abN0 HER2-positive breast cancers. Such information must be obtained from retrospective series3-7 or prospective cohort studies.8,9 In addition, the selection of chemotherapy regimens for patients with small HER2-positive tumors is important, and we observed heterogeneous outcomes among the trials for the hormone receptor (HR)–negative cohort, which may be due in part to the difference in timing of chemotherapy. Thus, we hesitate to make any additional conclusions, because patients were not randomly assigned to chemotherapy regimens. Finally, we agree that additional analyses of retrospective series and prospective cohort studies will be important to identify additional patient subgroups that may warrant less (or more) intensive treatments. For example, in a previous meta-analysis of five of the adjuvant randomized trastuzumab trials, we identified a subgroup of patients with HR-positive, HER2-positive tumors of 2 cm or smaller, and one or no positive lymph nodes, who had excellent prognoses when treated with trastuzumab and chemotherapy with or without endocrine therapy; the 5-year disease-free survival was 91%, and the 5-year overall survival was 97%.10 These results, we hope, will provide a benchmark for the design of future trials to evaluate less aggressive treatment approaches.
Jo Anne Zujewski
Ciara C. O’Sullivan National Cancer Institute, National Institutes of Health, Bethesda, MD
Frontier Science, Inverness-shire, Scotland
National Cancer Institute, National Institutes of Health, Bethesda, MD
Richard D. Gelber Harvard Medical School, Harvard T.H. Chan School of Public Health, Dana-Farber Cancer Institute, and Frontier Science and Technology Research Foundation, Boston, MA
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org REFERENCES 1. Oguz A, Keskin GS, Colak D, et al: Treatment of lymph node–negative, earlystage HER2-positive breast cancer. J Clin Oncol 34:639-640, 2016 2. O’Sullivan CC, Bradbury I, Campbell C, et al: Efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2-positive early breast cancer and tumors # 2 cm: A meta-analysis of the randomized trastuzumab trials. J Clin Oncol 33:2600-2608, 2015 ´ 3. Rodrigues MJ, Peron J, Frenel JS, et al: Benefit of adjuvant trastuzumabbased chemotherapy in T1ab node-negative HER2-overexpressing breast carcinomas: A multicenter retrospective series. Ann Oncol 24:916-924, 2013 4. Chia S, Norris B, Speers C, et al: Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of nodenegative breast cancers. J Clin Oncol 26:5697-5704, 2008 5. Curigliano G, Viale G, Bagnardi V, et al: Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer. J Clin Oncol 27:5693-5699, 2009 6. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al: High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2positive, node-negative tumors 1 cm or smaller. J Clin Oncol 27:5700-5706, 2009 7. Fehrenbacher L, Capra AM, Quesenberry CP Jr. et al: Distant invasive breast cancer recurrence risk in human epidermal growth factor receptor 2-positive T1a and T1b node-negative localized breast cancer diagnosed from 2000 to 2006: A cohort from an integrated health care delivery system. J Clin Oncol 32:2151-2158, 2014 8. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015 9. Vaz-Luis I, Ottesen RA, Hughes ME, et al: Outcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: A multiinstitutional study. J Clin Oncol 32:2142-2150, 2014 10. O’Sullivan CC, Holmes E, Spielmann M, et al: The prognosis of small HER2positive breast cancers: A meta-analysis of the randomized trastuzumab trials. Presented at the 36th CTRC-AACR San Antonio Breast Cancer Symposium, San Antonio, TX, December 10-14, 2013
DOI: 10.1200/JCO.2015.65.1034; published online ahead of print at www.jco.org on December 7, 2015
n n n
640
© 2015 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 34, No 6 (February 20), 2016: pp 640
Downloaded from jco.ascopubs.org on June 21, 2016. For personal use only. No other uses without permission. Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
Correspondence
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Reply to A. Oguz et al. The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 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. Ciara C. O’Sullivan No relationship to disclose
Jo Anne Zujewski No relationship to disclose
Eileen Holmes No relationship to disclose
Richard D. Gelber Research Funding: AstraZeneca (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Roche (Inst), Celgene (Inst), Merck (Inst), Pfizer (Inst)
Christine Campbell No relationship to disclose Ian Bradbury No relationship to disclose
www.jco.org
© 2015 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on June 21, 2016. For personal use only. No other uses without permission. Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
