Online Appendix

Table 1: Summary of RCTs regarding trastuzumab for the first-line treatment of HER2+ metastatic breast cancer

Trial / Eligibility Criteria* / Treatment and number of patients
H0648g[15] / Characteristics: Women with HER2+ metastatic breast cancer. Excluded if they had bilateral breast cancer, untreated brain metastases, osteoblastic bone metastases, pleural effusion or ascites as the only evidence of disease, a second type of primary cancer, or a Karnofsky score < 60.
HER2+ test:IHC 2+ or 3+
Prior therapy: Not reported, but unlikely HER2 therapy given timing of trial. / If prior adjuvant AC
Trastuzumab4mg/kg day 1 then 2mg/kg qw + paclitaxel175mg/m2q3w (N=92) vs paclitaxel175mg/m2q3w alone (N=96)
If no prior adjuvant AC
Trastuzumab4mg/kg day 1 then 2mg/kg qw + AC (doxorubicin 60mg/m2q3w or epirubicin75mg/m2q3w) + cyclophosphamide 600mg/m2q3w (N=143) vs AC (doxorubicin 60mg/m2q3w or epirubicin75mg/m2q3w) + cyclophosphamide 600mg/m2q3w alone (N=138)
M77001[16] / Characteristics: Women aged 18 to 70 years with HER2+ metastatic breast cancer.Baseline LVEF > 50%. ECOG performance status ≤ 2 and life expectancy ≥ 12 weeks. Excluded if brain or leptomeningeal metastases.
HER2+ test:IHC 3+ and/or FISH+
Prior therapy: Excluded if prior chemotherapy for metastatic breast cancer (neo-adjuvant anthracyclines allowed) or any prior taxanes or anti-HER therapy. / Trastuzumab4mg/kg day 1 then 2mg/kg qw + docetaxel100mg/m2q3w (N=92) vs docetaxel100mg/m2q3w alone (N=94)
Gasparini et al. (2007)[18] / Characteristics: Women aged ≥18 years with HER2+ metastatic breast cancer. Baseline LVEF > 50%.ECOG performance status ≤ 2 and life expectancy >3 months. Excluded if brain or bone metastases are the only site of disease, a history of other cancers (except in situ cervix cancer radically resected and non-melanoma skin cancer).
HER2+ test:IHC 2+ or 3+
Prior therapy: Excluded if prior chemotherapy for metastatic breast cancer (adjuvant anthracyclines and/or taxane and relapsed >12 months following the end of chemotherapy allowed). / Trastuzumab4mg/kg day 1 then 2mg/kg qw + paclitaxel80mg/m2qw (N=92) vs paclitaxel80mg/m2qw alone (N=96)
TAnDEM[17] / Characteristics: Postmenopausal women with HER2+ and hormone receptor + (ER+ and/or PgR+) metastatic breast cancer. Baseline LVEF > 50%, ECOG performance status ≤ 1. Excluded if clinical or radiologic evidence of central nervous system metastases or history of another malignancy.
HER2+ test:IHC 3+ and/or FISH+
Prior therapy: Excluded if prior chemotherapy for metastatic breast cancer, adjuvant chemotherapy within 6 months, or prior anti-HER2 therapy (allowed tamoxifen as adjuvant or hormonal therapy for metastatic breast cancer or anastrozole if begun <4 weeks before random assignment). / Trastuzumab4mg/kg day 1 then 2mg/kg qw + anastrozole1mgqd (N=103) vs anastrozole1mgqd (N=104)
TRAVIOTA[20] / Characteristics: Patients with HER2+ metastatic breast cancer. Baseline LVEF ≥ 50%. ECOG performance status ≤ 2 and life expectancy > 6 months. Excluded if history of brain metastases, leptomeningeal metastases or other cancers (except in situ cervix cancer and non-melanoma skin cancer).
HER2+ test:IHC 3+ and/or FISH+
Prior therapy: Excluded if prior chemotherapy for metastatic breast cancer, adjuvant chemotherapy within 6 months, or adjuvant trastuzumab within 12 months. / Trastuzumab4mg/kg day 1 then 2mg/kg qw + vinorelbine25mg/m2qw (N=41) vs trastuzumab4mg/kg day 1 then 2mg/kg qw +
-paclitaxel80mg/m2qw (N=14)
-docetaxel35mg/m2 on weeks 1, 2, 3, 5, 6, 7 (N=24)
Two patients also received carboplatin in addition to paclitaxel.
HERNATA[19] / Characteristics: Patients 18 to 75 years of age with HER2+ metastatic breast cancer or locally advanced breast cancer. Baseline LVEF normal, ECOG performance status ≤ 2 and life expectancy ≥ 12 weeks. Excluded if brain metastases or other cancer.
HER2+ test: IHC 3+ and/or FISH+
Prior therapy: Excluded if prior chemotherapy for metastatic breast cancer, adjuvant chemotherapy or trastuzumab within 12 months. / Trastuzumab8mg/kg day 1 then 6mg/kg q3w + docetaxel100mg/m2q3w (N=143) vs trastuzumab8mg/kg day 1 then 6mg/kg q3w + vinorelbine30mg/m2 or 35mg/m2days 1 and 8 q3w (N=141)

AC: Anthracycline; ECOG: Eastern Cooperative Oncology Group; ER: Oestrogen Receptor; FISH: Fluorescence In Situ Hybridization; IHC: Immunohistochemistry; LVEF: Left Ventricular Ejection Fraction; N: number of patients; PgR: Progesterone Receptor; q3w: once three weekly; qd: once daily; qw: once weekly.

*May not be comprehensive.

Table 2: Chemotherapies administered prior to treatment with trastuzumab

Variable / Herceptin Program
N=3617 / Clinical trials
Number of prior chemotherapies / NR for all trials
Mean (SD) / 1.5 (1.6)
Median (range)
> 1 chemotherapy, % / 1 (0 – 10)
78.4
Prior treatment with trastuzumab (e.g. for EBC or locally advanced breast cancer), % / 4.6 / H0648g: NR (presumably 0%)
M77001: 0%
Gasparini et al. (2007): NR
TANDEM: 0%
TRAVIOTA: NR
HERNATA: 0.4%
Prior treatment with a taxane, % / 20.0 / H0648g: NR
M77001: 0%
Gasparini et al. (2007): 6.5%
TANDEM: NR
TRAVIOTA: 19.7%
HERNATA: 1.4%
Prior treatment with an anthracycline, % / 25.2 / H0648g: NR
M77001: 59.7%
Gaspariniet al. (2007): 56.9%
TANDEM: 46.3%
TRAVIOTA: 33.3%
HERNATA: 37.7%
Prior treatment with an aromatase inhibitor, % / 24.4 / H0648g: NR (57.8% hormonal therapy)
M77001: NR (45.2% prior hormonal therapy)
Gasparini et al. (2007): NR
TANDEM: NR (63.3% prior hormonal therapy)
TRAVIOTA: NR
HERNATA: NR (53.2% prior hormonal therapy for adjuvant or locally advanced/metastatic disease)
Prior treatment with vinorelbine, n(%) / 1.8 / NR for all trials

EBC: early breast cancer. NR: not reported; SD: standard deviation. Source: [15-20]

Table 3: Chemotherapy following progression based on Herceptin Program

Chemotherapy / Patients treated following progression, n (%)
Any chemotherapy / 1,983 (64.1)
Trastuzumab via the Herceptin Program / 1,395 (45.1)
Lapatinib / 275 (8.9)
Capecitabine / 929 (30.0)
Paclitaxel / 663 (21.4)
Docetaxel / 536 (17.3)
Vinorelbine / 533 (17.2)
Aromatase inhibitor / 454 (14.7)
Gemcitabine / 252 (8.1)
Doxorubicin / 243 (7.8)
Carboplatin / 195 (6.3)
Other chemotherapy / 394 (12.7)
All patients who progressed before 31 March 2010 / 3,096 (100.0)

Note: Patients may receive more than one chemotherapy.

Table 4: Concomitant chemotherapies administered based on Herceptin Program

Initial concomitant chemotherapies (pre-progression), n (%)
N=3617 / Post-progression concomitant chemotherapies, n (%) / All concomitant chemotherapies, n (%)
Any taxane / 1,506 (41.6) / 698 (19.3) / 1,939 (53.6)
Docetaxel / 846 (23.4) / 376 (10.4) / 1,117 (30.9)
Paclitaxel and nab-paclitaxel / 690 (19.1) / 385 (10.6) / 991 (27.4)
Other taxane / 0 (0.0) / 0 (0.00) / 0 (0.00)
Any hormonal therapy / 828 (22.9) / 200 (5.5) / 925 (25.6)
Aromatase inhibitor / 714 (19.7) / 163 (4.5) / 797 (22.0)
Tamoxifen / 104 (2.9) / 26 (0.7) / 128 (3.5)
Other hormonal therapy / 149 (4.1) / 43 (1.2) / 168 (4.6)
Any other concomitant chemotherapy / 462 (12.8) / 662 (18.3) / 982 (27.1)
Any anthracycline / 76 (2.1) / 68 (1.9) / 134 (3.7)
Doxorubicin and doxorubicin hydrochloride-pegylated liposomal / 44 (1.2) / 49 (1.4) / 87 (2.4)
Epirubicin / 27 (0.7) / 15 (0.4) / 40 (1.1)
Other anthracycline (e.g. mitozantrone) / 5 (0.1) / 4 (0.1) / 8 (0.2)
Nitrogen mustard analogues (e.g. cyclophosphamide) / 48 (1.3) / 24 (0.7) / 69 (1.9)
Platinum compounds (e.g. cisplatin and carboplatin) / 113 (3.1) / 105 (2.9) / 206 (5.7)
Cisplatin / 3 (0.1) / 4 (0.1) / 7 (0.2)
Carboplatin / 110 (3.0) / 101 (2.8) / 199 (5.5)
Other platinum compound / 1 (0.0) / 1 (0.0) / 2 (0.1)
Capecitabine / 81 (2.2) / 309 (8.5) / 365 (10.1)
Gemcitabine / 56 (1.5) / 85 (2.4) / 122 (3.4)
Vinorelbine / 91 (2.5) / 263 (7.3) / 346 (9.6)
Lapatinib / 0 (0.0) / 4 (0.1) / 4 (0.1)
Trastuzumab funded through the PBS (for EBC or locally advanced breast cancer) / 6 (0.2) / 0 (0.0) / 6 (0.2)
Any other antineoplastic / 14 (0.4) / 19 (0.5) / 27 (0.7)
Immunostimulants / 42 (1.2) / 15 (0.4) / 53 (1.5)
Methotrexate / 9 (0.2) / 17 (0.5) / 25 (0.7)
Other immunosuppressants (excluding methotrexate) / 3 (0.1) / 4 (0.1) / 7 (0.2)
At least one of: docetaxel, paclitaxel/nab-paclitaxel, any anthracycline, an aromatase inhibitor or vinorelbine / 2,038 (56.3) / 909 (25.1) / 2,404 (66.5)
Another chemotherapy / 151 (4.2) / 163 (4.5) / 157 (4.3)
Monotherapy / 1,428 (39.5) / 2,545 (70.4) / 1,056 (29.2)
All patients / 3,617 (100.0) / 3,617 (100.0) / 3,617 (100.0)

Note: Patients may receive more than one chemotherapy.

EBC: early breast cancer.

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