1. Supplementary Figure 1A

2. R 2 = 0.9694 p < 0.0001 qRT-PCR Illumina BeadChip Supplementary Figure 1B 3 2 1 0 -2 -3 -2 -1 0 1 2 3 4

3. TrastuzumabPertuzumabCombination PCNA(ILMN_1706958)1.03 -1.03DNA Replication UBE2C(ILMN_1742958)-1.04-1.071.04Cell cycle, mitosis CKS2(ILMN_1756326)-1.131.07-1.08Cell cycle CKS2(ILMN_2072296)-1.071.021.05Cell cycle TYMS(ILMN_1806040)-1.22*1.00-1.04DNA replication FEN1(ILMN_2160929)-1.21*-1.05-1.09DNA repair and synthesis FEN1(ILMN_1755834)-1.16*1.01-1.13*DNA repair and synthesis ZWINT(ILMN_1653209)-1.13*-1.08-1.06Cell cycle, spindle RFC4(ILMN_2370365)-1.17*-1.03-1.08DNA replication and repair UBE2C(ILMN_2265654)-1.17*-1.061.01Cell cycle, mitosis TOP2A(ILMN_1686097)-1.12-1.041.06DNA replication AURKA(ILMN_2357438 STK6)-1.20*-1.131.00Cell cycle, spindle AURKA(ILMN_1680955 STK5)-1.18-1.06-1.02Cell cycle, spindle ZWINT(ILMN_2362549)-1.09-1.071.05Cell cycle, spindle HMGB2(ILMN_1654268)-1.14-1.14*1.05Chromatin HMGB2(ILMN_2219712)-1.21-1.131.09Chromatin SPAG5(ILMN_2141259 DEEPEST)-1.21*-1.08-1.03Cell cycle PCNA(ILMN_1694177)-1.13-1.05-1.11DNA Replication BUB1B(ILMN_1797307 MAD3L)-1.19*-1.13*-1.14*Cell cycle, mitosis RFC4(ILMN_1724489)-1.17*-1.10* DNA replication and repair NDC80(ILMN_1664511 HEC)-1.17-1.10-1.05Cell cycle spindle UBE2C(ILMN_1714730)-1.161.031.05Cell cycle, mitosis UBE2C(ILMN_2301083)-1.121.021.09Cell cycle, mitosis ZWINT(ILMN_2362545)-1.10-1.071.08Cell cycle, spindle GINS1(ILMN_1697751 KIAA0186)-1.071.01-1.12Unknown ZWINT(ILMN_1673117)-1.01-1.02Cell cycle, spindle PCNA(ILMN_1685682)1.05-1.01-1.05DNA Replication PHLDA2(ILMN_1671557)1.081.131.40*Fas expression HIST1H4C(ILMN_2075334 H4FG)1.011.08Chromatin CCNG2(ILMN_1747244)1.15*-1.081.05 CCNG2(ILMN_2228732)1.05-1.22*-1.01 Trastuzumab Pertuzumab Combined Supplementary Figure 2A

4. TrastuzumabPertuzumabCombination HER2+ breast cancer patients KIAA1549(ILMN_1728060)-1.021.01-1.01Higher in pCR PSMD11(ILMN_1800952)-1.211.03-1.03Higher in non-pCR SYNCRIP(ILMN_1727740)-1.11*-1.11Higher in pCR LAMA3(ILMN_2293594)-1.07*-1.03-1.04Higher in non-pCR GRHL2(ILMN_2060145)-1.03-1.011.02Higher in pCR P2RX1(ILMN_1758529)-1.04-1.03 Higher in non-pCR SENP7(ILMN_1778294)-1.03-1.06Higher in pCR PRKACA(ILMN_1786195)-1.07-1.05-1.02Higher in non-pCR DERL1(ILMN_2209748)-1.01 -1.02Higher in non-pCR PPP2CA(ILMN_2196097)1.02-1.011.01Higher in non-pCR SENP7(ILMN_2382354)1.05-1.25*1.03Higher in pCR CDC14A(ILMN_1774930)-1.06-1.051.01Higher in non-pCR SENP8(ILMN_1767690)-1.01 -1.08Higher in non-pCR WEE1(ILMN_1778561)-1.06*-1.041.00Higher in pCR CDC14A(ILMN_2244653)-1.09*-1.08-1.06Higher in non-pCR PEX19(ILMN_1658759)-1.05 -1.10Higher in non-pCR ZNF146(ILMN_2054442)-1.02-1.19* Higher in pCR CCDC123(ILMN_1679971)-1.11*-1.10*-1.14*Higher in pCR C5orf3(ILMN_1675701)-1.10*-1.08-1.11Higher in non-pCR PPP2CA(ILMN_1722858)-1.05-1.03 Higher in non-pCR SLC30A6(ILMN_1699365)-1.08-1.05-1.10Higher in non-pCR CDC14A(ILMN_1655983)-1.02-1.03-1.02Higher in non-pCR LAMA3(ILMN_1704247)1.001.17*-1.18*Higher in non-pCR LAMA3(ILMN_2406035)1.311.47*-1.54*Higher in non-pCR LAMA3(ILMN_1688892)1.161.34*-1.44*Higher in non-pCR STX1A(ILMN_1760160)1.04-1.04Higher in pCR CDC14A(ILMN_2324537)-1.011.02-1.01Higher in non-pCR FLJ20160(ILMN_1710209)1.011.031.24*Higher in non-pCR CDC14A(ILMN_1774557)1.021.09*1.01Higher in non-pCR PITPNA(ILMN_1715804)1.021.031.05Higher in non-pCR CTNS(ILMN_1807719)-1.021.091.12Higher in non-pCR SLC35A4(ILMN_2105966)1.021.131.14Higher in non-pCR NFE2L1(ILMN_1739450)1.051.031.19Higher in non-pCR ZNF146(ILMN_1699423)1.041.011.02Higher in pCR GPR22(ILMN_1684865)1.121.16*1.11*Higher in pCR CDC14A(ILMN_1739164)1.11*1.041.03Higher in non-pCR CTNS(ILMN_1738010)-1.021.041.05Higher in non-pCR PRKACA(ILMN_2395314)1.03-1.031.02Higher in non-pCR CTNS(ILMN_1776132)1.02-1.031.03Higher in non-pCR SLC30A6(ILMN_2151168)1.021.001.06Higher in pCR Trastuzumab Pertuzumab Combined Supplementary Figure 2B

5. Either HER2-inhibitor alone Trastuzumab alone AND combination Combination only Trastuzumab alone Pertuzumab alone Control Trastuzumab Pertuzumab Combined JUN, JUP DST, CDKN1A, CLIC6 JUN, SERPIN-A1/B5, MMP13, KRT-6A/16/7, ANXA8, PAK6 KRT5, ERBB3, CDH1, FOXO1 LCN2, KLK11 CD9, KRT14 CD36, CD36, CASP1 NRG4 PAK1 LAMA3 FOS, DUSP1, SNAI2 IL4R, CCL26, GADD45 CAV2, JAG1 IL8, IL8 TGFBI, SPARC CDH6, CAV1, CXCL1 LAMC2, LAMC2 IL6, IL15 GSTA1, GSTA2 ESR1 CDH17 TFF2, TFF3 Supplementary Figure 2C Pertuzumab alone AND combination Data from Ghosh et al. (2010) Cancer Research 71:1871-1882 Both HER2 inhibitors AND combination Control.1 Control.2AP1510.3AP1510.2AP1510.3Heregulin.1Heregulin.2Heregulin.3TGFalpha.1TGFalpha.2TGFalpha.3 Control Trastuzumab Pertuzumab Combined HER2- HER2 HER3- HER2 HER1- HER2 Homo- or Heterodimers

6. Control Trastuzumab Pertuzumab Combined Supplementary Figure 2D Heatmap from Ghosh et al. (2010) Cancer Research 71:1871-1882 Control.1 Control.2AP1510.3AP1510.2AP1510.3Heregulin.1Heregulin.2Heregulin.3TGFalpha.1TGFalpha.2TGFalpha.3 HER2- HER2 HER3- HER2 HER1- HER2 Homo- or Heterodimers

7. SKOV3 (2.15) HOX486 (0.89) HOX516 (1.2) HOX424 (7.75) OV1002 (0.94) HOX493 (0.575) Supplementary Figure 3