Clinical outcome of HER2-positive breast cancer by FcγR polymorphisms
| FcγRIIIa-158 (CD16A-158) | FcγRIIa-131 (CD32A-131) | FcγRIIb-232 (CD32B-232) | |||||||||||||||
| VV | VF | FF | V carriers | F carriers | HH | HR | RR | H carriers | R carriers | II | TI | TT | I carriers | T carriers | |||
| Neoadjuvant | |||||||||||||||||
| Phase II CHER- LOB trial (N=73)55 | Arm A: CTX+trast | pCR rate | NR | NR | 2/8 (25%) | 3/11 (27%) | NR | NR | NR | 1/4 (25%) | 4/15 (27%) | NR | NR | NR | NR | NR | NR |
| Arm B: CTX+lapa | NR | NR | 3/6 (50%) | 4/18 (22%) | NR | NR | NR | 3/6 (43%) | 4/18 (22%) | NR | NR | NR | NR | NR | NR | ||
| Arm C: CTX+trast +lapa | NR | NR | 5/12 (42%) | 12/18 (67%) | NR | NR | NR | 2/3 (67%) | 15/27 (56%) | NR | NR | NR | NR | NR | NR | ||
| Statistical analysis | V carriers versus F/F Arm A: p=0.91* Arm B: p=0.23* Arm C: p=0.18* Arm A versus arm B V carriers: p=0.621* F/F: p=0.683* Arm A versus arm C V carriers: p=0.043* F/F: p=0.642* Arm B versus arm C V carriers: p=0.012* F/F: p=0.737* An interaction between Arm C and FcγRIIIa-158V allele was found for pCR (p=0.002) | H carriers versus R/R Arm A: p=0.94* Arm B: p=0.23* Arm C: p=0.71* No correlation of FcγRIIa polymorphism with pCR rate was observed across arms | NR | ||||||||||||||
| DFS | Arms A+B versus C F/F: p=0.870† Arms C versus A+B V carriers: p=0.059† | Similar DFS across arms by FcγRIIa polymorphism | NR | ||||||||||||||
| Small prospective study (N=15)59 | CTX+trast | pCR rate | 4/7 (57%) | 1/6 (17%) | 0/2 (0%) | 5/13 (38%) | 1/8 (13%) | 5/7 (71%) | 0/6 (0%) | 0/2 (0%) | 5/13 (38%) | 0/8 (0%) | NR | NR | NR | NR | NR |
| Statistical analysis | p=0.45 (V/V vs F carriers)* | p=0.015 (H/H vs R carriers)* | NR | ||||||||||||||
| Small prospective study (N=26)113 | CTX+trast | pCR rate | 3/12 (25%) | 8/12 (67%) | 1/12 (8%) | 11/12 (92%) | 9/12 (75%) | 3/12 (25%) | 3/12 (25%) | 6/12 (50%) | 6/12 (50%) | 9/12 (75%) | NR | NR | NR | NR | NR |
| Statistical analysis | p=0.590 (F carriers vs VV or V/F)* | p=0.012 (R/R vs HH or H/R)* | NR | ||||||||||||||
| Adjuvant | |||||||||||||||||
| Phase III NSABP B-31 trial (N=1156)45 | Arm A: CTX | DFS | Arm B versus arm A: HR: 0.12 (p <0.001)† | Arm B versus arm A: HR: 0.34 (p <0.001)† | Arm B versus arm A: HR: 0.71 (p =0.05)† | Arm B versus arm A: HR: 0.31 (p <0.001)† | NR | Arm B versus arm A: HR: 0.31 (p <0.001)† | Arm B versus arm A: HR: 0.50 (p <0.001)† | Arm B versus arm A: HR: 0.57 (p =0.02)† | Arm B versus arm A: HR: 0.43 (p <0.001)† | NR | NR | NR | NR | NR | NR |
| Arm B: CTX +trast | NR | NR | NR | NR | NR | ||||||||||||
| Statistical analysis | Tx-interaction test indicates an association between FcγRIIIa-158V carriers (vs F/F) and benefit from trast (p<0.001) | Tx-interaction test indicates no association between FcγRIIa-131H carriers (vs R/R) and benefit from trast (p=0.24) | NR | ||||||||||||||
| Phase III BCIRG- 006 trial (N=1189)46 | Arm A: CTX (dox/cyclo/doce) | DFS events | 16/56 | 33/149 | 31/176 | 49/205 | 64/325 | 26/110 | 36/182 | 19/95 | 62/292 | 55/277 | NR | NR | NR | NR | NR |
| Arm B: CTX (dox/cyclo/doce) +trast | DFS events | 20/113 | 63/322 | 74/373 | 83/435 | 137/695 | 41/213 | 85/415 | 39/203 | 126/628 | 124/618 | NR | NR | NR | NR | NR | |
| Arm C: CTX (doce/carbo/) +trast | NR | NR | NR | NR | NR | ||||||||||||
| Statistical analysis | V/V versus V/F versus F/F Arm A: p=0.33† Arm B: p=0.94† Arm C: p=0.96† Arm B+C: p=0.98† Arm B+C versus arm A V/V: p=0.13† V/F: p=0.422† F/F: p=0.81† Tx-interaction test indicates no association between FcγRIIIa polymorphism and benefit from trast | H/H versus H/R versus R/R Arm A: p=0.81† Arm B: p=0.47† Arm C: p=0.98† Arm B+C: p=0.76† Arm B+C versus arm A H/H: p=0.35† H/R: p=0.985† R/R: p=0.58† Tx-interaction test indicates no association between FcγRIIa polymorphism and benefit from trast | NR | ||||||||||||||
| Phase III NCCTG-N9831 (N=1325)56 | Arm A: CTX | DFS events | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | 92/323 | NR | NR | NR | 15/95 |
| Arm B+C: CTX +sequential (B) or concurrent (C) trast | 21/116 | 65/402 | 74/388 | 86/518 | 139/790 | 38/221 | 80/462 | 42/223 | 118/683 | 122/685 | 123/ 701 | 31/180 | 4/23 | 154/881 | 35/203 | ||
| Statistical analysis | Arms B+C versus arm A: V/V: p=0.24† V/F: p<0.001† F/F: p=0.20† V/V versus F/F Arm B+C: p=0.52† Tx-interaction test indicates no association between FcγRIIIa polymorphism and benefit from trast | Arms B+C versus arm A: H/H: p=0.04† H/R: p=0.004† R/R: p=0.10† H/H versus R/R Arm B+C: p=0.97† Tx-interaction test indicates no association between FcγRIIa polymorphism and benefit from trast | Arms B+C versus arm A: I/I: p<0.0001† I/T: p=0.86† T/T: p=0.87† T carriers: p=0.81† I/I versus T/T Arm B+C: p=0.96† Tx-interaction test indicates an association between FcγRIIb-232I homozygotes (vs T carriers) and benefit from trast (p=0.03) | ||||||||||||||
| Phase III UNICANCER- PACS04 (N=132)115 | CTX followed by trast | 5-year EFS rate | 91% | 87% | 83% | 87% | 85% | 85% | 93% | 70% | 90% | 86% | NR | NR | NR | NR | NR |
| Statistical analysis | p=0.8291 (V carriers vs F/F)† p=0.8769 (F carriers vs V/V)† | p=0.0278 (H/H carriers vs R/R)† p=0.6320 (R/R carriers vs H/H)† | NR | ||||||||||||||
| Metastatic | |||||||||||||||||
| Retrospective analysis (N=54)54 | CTX+trast | ORR | 9/11 (82%) | 11/26 (42%) | 6/17 (35%) | 20/37 (54%) | 17/43 (40%) | 7/10 (70%) | 15/34 (44%) | 4/10 (40%) | 22/44 (50%) | 19/44 (43%) | 24/44 (55%) | 1/6 (17%) | 1/4 (25%) | 25/50 (50%) | 2/10 (20%) |
| Statistical analysis | p=0.03* | p=0.17* | p=0.10* | ||||||||||||||
| Median PFS | Not reached | 15.0 mo | 11.1 mo | NR | 12.9 mo | 29.5 mo | 16.8 mo | 10.0 mo | NR | 13.4 mo | 15.0 mo | 22.0 mo | 9.0 mo | NR | NR | ||
| Statistical analysis | NR | p =0.008† | p =0.005† | NR | p= 0.0035† | NR | p=0.44† | p=0.04† | NR | p=0.25† | p=0.98† | ||||||
| Phase III SOPHIA trial (N=506)58 | Arm A: CTX+marge | Median PFS | 4.8 mo | 6.3 mo | 8.2 mo | NR | 6.9 mo | 5.6 mo | 6.9 mo | 5.7 mo | NR | NR | 5.8 mo | 6.0 mo | NR | NR | NR |
| Arm B: CTX+trast | 5.6 mo | 4.3 mo | 5.6 mo | NR | 5.1 mo | 4.1 mo | 5.6 mo | 5.5 mo | NR | NR | 5.5 mo | 5.5 mo | NR | NR | NR | ||
| Statistical analysis | p=0.110† | p =0.055† | p =0.080† | NR | p =0.005† | NA | NA | NA | NR | NR | NA | NA | NR | NR | NR | ||
| Arm A: CTX+marge | Median OS | 19.7 mo | 25.5 mo | 23.3 mo | NR | 23.7 mo | 19.6 mo | 23.7 | 32.8 mo | NR | NR | 23.3 mo | 25.1 mo | NR | NR | NR | |
| Arm B: CTX+trast | 33.3 mo | 20.0 mo | 18.4 mo | NR | 19.4 mo | 18.8 mo | 21.0 | 20.0 mo | NR | NR | 20.5 mo | 17.9 mo | NR | NR | NR | ||
| Statistical analysis | p=0.157† | p =0.498† | p =0.062† | NR | p =0.087† | NA | NA | NA | NR | NR | NA | NA | NR | NR | NR | ||
| Small prospective study (N=35)59 | Trast | ORR | 6/15 (40%) | 1/17 (6%) | 1/3 (33%) | 7/32 (22%) | 2/20 (10%) | 6/15 (40%) | 2/18 (12%) | 0/2 (0%) | 8/33 (24%) | 2/20 (10%) | NR | NR | NR | NR | NR |
| Statistical analysis | p=0.053 (V/V vs F carriers)* | p=0.043 (H/H vs R carriers)* | NR | ||||||||||||||
| Median PFS | 8.5 mo | NR | NR | NR | 5.3 mo | 9.2 mo | NR | NR | NR | 3.5 mo | NR | NR | NR | NR | NR | ||
| Statistical analysis | p=0.37 (V/V vs F carriers)† | p=0.034 (H/H vs R carriers)† | NR | ||||||||||||||
*Fisher’s exact test.
†Log-rank test.
BCIRG, Breast Cancer International Research Group; Carbo, carboplatin; CTX, chemotherapy; cyclo, cyclophosphamide; DFS, disease-free survival; doce, docetaxel; dox, doxorubicin; EFS, event-free survival; FcγR, fragment crystallizable gamma receptor; HER2, human epidermal growth factor receptor 2; lapa, lapatinib; marge, margetuximab; mo, months; NA, not available; NCCTG, North Central Cancer Treatment Group; NR, not reported; NSABP, National Surgical Adjuvant Breast and Bowel Project; ORR, objective response rate; OS, overall survival; pCR, pathological complete response; PFS, progression-free survival; trast, trastuzumab; tx, treatment.