Low-dose oral cyclophosphamide and methotrexate maintenance for hormone receptor-negative early breast cancer

International Breast Cancer Study Group Trial 22-00

Marco Colleoni, Kathryn P. Gray, Shari Gelber, István Láng, Beat Thürlimann, Lorenzo Gianni, Ehtesham A. Abdi, Henry L. Gomez, Barbro K. Linderholm, Fabio Puglisi, Carlo Tondini, Elena Kralidis, Alexandru Eniu, Katia Cagossi, Daniel Rauch, Jacquie Chirgwin, Richard D. Gelber, Meredith M. Regan, Alan S. Coates, Karen N. Price & 2 others Giuseppe Viale, Aron Goldhirsch

Research output: Contribution to journalArticle

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Abstract

Purpose: To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer. Patients and Methods: International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths. Results: After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06; P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%). Conclusion: CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.

Original languageEnglish
Pages (from-to)3400-3408
Number of pages9
JournalJournal of Clinical Oncology
Volume34
Issue number28
DOIs
Publication statusPublished - Oct 1 2016

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Methotrexate
Cyclophosphamide
Maintenance
Hormones
Breast Neoplasms
Disease-Free Survival
Phase III Clinical Trials
Leukopenia
Progesterone Receptors
Adjuvant Chemotherapy
Transaminases
Ambulatory Surgical Procedures
Estrogen Receptors
Breast
Randomized Controlled Trials
Immunohistochemistry
Recurrence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Low-dose oral cyclophosphamide and methotrexate maintenance for hormone receptor-negative early breast cancer : International Breast Cancer Study Group Trial 22-00. / Colleoni, Marco; Gray, Kathryn P.; Gelber, Shari; Láng, István; Thürlimann, Beat; Gianni, Lorenzo; Abdi, Ehtesham A.; Gomez, Henry L.; Linderholm, Barbro K.; Puglisi, Fabio; Tondini, Carlo; Kralidis, Elena; Eniu, Alexandru; Cagossi, Katia; Rauch, Daniel; Chirgwin, Jacquie; Gelber, Richard D.; Regan, Meredith M.; Coates, Alan S.; Price, Karen N.; Viale, Giuseppe; Goldhirsch, Aron.

In: Journal of Clinical Oncology, Vol. 34, No. 28, 01.10.2016, p. 3400-3408.

Research output: Contribution to journalArticle

Colleoni, M, Gray, KP, Gelber, S, Láng, I, Thürlimann, B, Gianni, L, Abdi, EA, Gomez, HL, Linderholm, BK, Puglisi, F, Tondini, C, Kralidis, E, Eniu, A, Cagossi, K, Rauch, D, Chirgwin, J, Gelber, RD, Regan, MM, Coates, AS, Price, KN, Viale, G & Goldhirsch, A 2016, 'Low-dose oral cyclophosphamide and methotrexate maintenance for hormone receptor-negative early breast cancer: International Breast Cancer Study Group Trial 22-00', Journal of Clinical Oncology, vol. 34, no. 28, pp. 3400-3408. https://doi.org/10.1200/JCO.2015.65.6595
Colleoni, Marco ; Gray, Kathryn P. ; Gelber, Shari ; Láng, István ; Thürlimann, Beat ; Gianni, Lorenzo ; Abdi, Ehtesham A. ; Gomez, Henry L. ; Linderholm, Barbro K. ; Puglisi, Fabio ; Tondini, Carlo ; Kralidis, Elena ; Eniu, Alexandru ; Cagossi, Katia ; Rauch, Daniel ; Chirgwin, Jacquie ; Gelber, Richard D. ; Regan, Meredith M. ; Coates, Alan S. ; Price, Karen N. ; Viale, Giuseppe ; Goldhirsch, Aron. / Low-dose oral cyclophosphamide and methotrexate maintenance for hormone receptor-negative early breast cancer : International Breast Cancer Study Group Trial 22-00. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 28. pp. 3400-3408.
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abstract = "Purpose: To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer. Patients and Methods: International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10{\%} positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths. Results: After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95{\%} CI, 0.66 to 1.06; P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95{\%} CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95{\%} CI, 0.49 to 1.05). Seventy-one (13{\%}) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14{\%}) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7{\%}), followed by leukopenia (2{\%}). Conclusion: CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.",
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T1 - Low-dose oral cyclophosphamide and methotrexate maintenance for hormone receptor-negative early breast cancer

T2 - International Breast Cancer Study Group Trial 22-00

AU - Colleoni, Marco

AU - Gray, Kathryn P.

AU - Gelber, Shari

AU - Láng, István

AU - Thürlimann, Beat

AU - Gianni, Lorenzo

AU - Abdi, Ehtesham A.

AU - Gomez, Henry L.

AU - Linderholm, Barbro K.

AU - Puglisi, Fabio

AU - Tondini, Carlo

AU - Kralidis, Elena

AU - Eniu, Alexandru

AU - Cagossi, Katia

AU - Rauch, Daniel

AU - Chirgwin, Jacquie

AU - Gelber, Richard D.

AU - Regan, Meredith M.

AU - Coates, Alan S.

AU - Price, Karen N.

AU - Viale, Giuseppe

AU - Goldhirsch, Aron

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Purpose: To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer. Patients and Methods: International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths. Results: After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06; P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%). Conclusion: CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.

AB - Purpose: To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer. Patients and Methods: International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths. Results: After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06; P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%). Conclusion: CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.

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