Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, node-negative breast cancer: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer.
OBJECTIVE
Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents.


METHODS
Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present.


RESULTS
Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor-absent, and endocrine receptor-present subtypes. No clear chemotherapy benefit was observed in endocrine receptor-present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor-present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor-absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor-present disease).


CONCLUSIONS
The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.
Colleoni
Marco
M
Research Unit in Medical Senology, Department of Medicine, European Institute of Oncology, Università degli Studi di Milano, Milan, Italy. marco.colleoni@ieo.it
Cole
Bernard F
BF
Viale
Giuseppe
G
Regan
Meredith M
MM
Price
Karen N
KN
Maiorano
Eugenio
E
Mastropasqua
Mauro G
MG
Crivellari
Diana
D
Gelber
Richard D
RD
Goldhirsch
Aron
A
Coates
Alan S
AS
Gusterson
Barry A
BA
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000378:metabolism*; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23
12829800
J Clin Oncol. 2009 Mar 10;27(8):1168-76
19204205
Nature. 2000 Aug 17;406(6797):747-52
10963602
Ann Oncol. 2008 Mar;19(3):465-72
17986623
Nat Rev Cancer. 2009 Feb;9(2):128-34
19132008
J Clin Oncol. 2006 Apr 20;24(12):1940-9
16622270
Lancet Oncol. 2009 May;10(5):522-7
19410197
JAMA. 2006 Apr 12;295(14):1658-67
16609087
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
11553815
Breast Cancer Res Treat. 2009 Jul;116(2):317-28
18839307
J Natl Cancer Inst. 2002 Jul 17;94(14):1054-65
12122096
J Clin Oncol. 2000 Jan;18(1):94-101
10623698
Ann Oncol. 2007 Jul;18(7):1177-84
17429101
J Clin Oncol. 1996 Jun;14(6):1885-94
8656257
J Natl Cancer Inst. 2008 Feb 6;100(3):207-12
18230798
Oncologist. 2007 Feb;12(2):142-50
17296808
N Engl J Med. 2005 Jun 2;352(22):2302-13
15930421
J Natl Cancer Inst. 2003 Dec 17;95(24):1833-46
14679153
J Clin Oncol. 2006 Mar 1;24(7):1037-44
16505422
J Natl Cancer Inst. 2008 Jan 2;100(1):14-20
18159072
J Clin Oncol. 1998 Apr;16(4):1358-62
9552037
Endocr Relat Cancer. 2005 Jul;12 Suppl 1:S125-33
16113089
Br J Cancer. 1977 Jan;35(1):1-39
831755
N Engl J Med. 2006 May 18;354(20):2103-11
16707747
J Clin Oncol. 2005 Oct 1;23(28):7212-20
16192605
J Clin Oncol. 2006 Dec 20;24(36):5664-71
17116941
Lancet. 1999 Jul 10;354(9173):130-1
10408495
J Natl Cancer Inst. 2006 Nov 1;98(21):1571-81
17077359
J Clin Oncol. 2008 Mar 20;26(9):1404-10
18349391
Trends Mol Med. 2006 Nov;12(11):537-44
17011236
N Engl J Med. 2007 Oct 11;357(15):1496-506
17928597
Cancer. 2007 Jan 1;109(1):25-32
17146782
Ann Oncol. 2009 Aug;20(8):1319-29
19535820
J Natl Cancer Inst. 2005 Sep 7;97(17):1254-61
16145046
J Clin Oncol. 1996 Oct;14(10):2738-46
8874335