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Best of SABCS: Treatment Update for HER2+ Disease: Changing Paradigms

Best of SABCS: Treatment Update for HER2+ Disease: Changing Paradigms. Sara A Hurvitz, MD, FACP Associate Professor of Medicine Director, Breast Oncology UCLA/ Jonsson Comprehensive Cancer Center. San Antonio Breast Cancer Symposium, December 6, 2018. Disclosures.

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Best of SABCS: Treatment Update for HER2+ Disease: Changing Paradigms

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  1. Best of SABCS: Treatment Update for HER2+ Disease: Changing Paradigms Sara A Hurvitz, MD, FACPAssociate Professor of MedicineDirector, Breast OncologyUCLA/Jonsson Comprehensive Cancer Center

  2. San Antonio Breast Cancer Symposium, December 6, 2018 Disclosures • Research Grant Support (paid to UCLA) • Ambryx, Bayer, Daiichi-Sankyo, Genentech/Roche, Immunomedics, Lilly, Macrogenics, Merrimack, Novartis, Pfizer, Seattle Genetics, Pieris, PUMA, Dignitana, OBI Pharma • Payments by pharma for medical writing on papers on which I am an author • Genentech/Roche, Pfizer, Novartis, Boehringer-Ingelheim, Amgen, Daiichi-Sankyo, Lilly, (and possibly others listed above in the future) • Honoraria: None This presentation is the intellectual property of the author/presenter. Contact them at shurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  3. HER2+ Breast Cancer • Identifying HER2-addicted disease: • Tackling equivocal FISH • Adjuvant T-DM1 KATHERINE • Natural history of trastuzumab-treated early disease: • Long term outcomes HER2+ HR+ breast cancer (N9831/B31) • Risk of CNS relapse after early stage disease (BCIRG006) • Novel combinations • CDK4/6i in HER2+ Disease (PATRICIA) • T-DM1 plus atezolizumab (KATE-2)

  4. Toward Understanding Equivocal HER2 HER2 status in HER2 equivocal breast cancers by FISH and 2013/2014 ASCO-CAP Guidelines: False positives owing to heterozygous deletions of alternative control loci Press M et al PD3-05

  5. Algorithm for Evaluation of HER2 Gene Amplification In situ hybridization (ISH) assay of the invasive component of a BC specimen using a dual-signal HER2 gene assay (dual-probe ISH)* HER2 testing (invasive component) by validated dual-probe ISH assay Batch controls and on-slide controls show appropriate hybridization HER2/CEP17ratio ≥2.0 HER2/CEP17ratio <2.0 Group 3 Average HER2copy number ≥6.0signals/cell Group 5 Average HER2copy number <4.0signals/cell Group 4 Average HER2copy number ≥4.0 and <6.0 signals/cell Group 1 Average HER2copy number ≥4.0signals/cell Group 2 Average HER2copy number <4.0signals/cell Additional work-up required Assess IHC using sections from the same tissue sample used for ISH • ISH • positive • ISH • negative IHC 0 or 1+ = HER2 negative with comment IHC 3+ = HER2 positive ICH 2+ = varies from Group 2 vs 3 vs 4 *recommended instead of single probe ISH assays. Wolff A et al J ClinOncol. 2018. May 30:JCO2018778738.

  6. Algorithm for Evaluation of HER2 Gene Amplification In situ hybridization (ISH) assay of the invasive component of a BC specimen using a dual-signal HER2 gene assay (dual-probe ISH) HER2 testing (invasive component) by validated dual-probe ISH assay Batch controls and on-slide controls show appropriate hybridization HER2/CEP17ratio >2.0 Group 2 Average HER2copy number <4.0signals/cell Press analysis: 0.7% of >10,000 patients. Rare. Usually IHC 0/1+. Did not have benefit from trastuzumab in BCIRG-006 study Additional work-up required Assess IHC using sections from the same tissue sample used for ISH DFS = disease-free survival; OS = overall survival. Press MF et al. J Clin Oncol 2016;34:3518-3528.

  7. Algorithm for Evaluation of HER2 Gene Amplification In situ hybridization (ISH) assay of the invasive component of a BC specimen using a dual-signal HER2 gene assay (dual-probe ISH) HER2 testing (invasive component) by validated dual-probe ISH assay Batch controls and on-slide controls show appropriate hybridization HER2/CEP17ratio <2.0 Group 3 Average HER2copy number ≥6.0signals/cell Press analysis: 0.5% of >10,000 patients. Rare. Unclear whether trastuzumab benefits, but standard remains to treat with trastuzumab Additional work-up required Assess IHC using sections from the same tissue sample used for ISH DFS = disease-free survival; OS = overall survival. Press MF et al. J Clin Oncol 2016;34:3518-3528.

  8. Algorithm for Evaluation of HER2 Gene Amplification In situ hybridization (ISH) assay of the invasive component of a BC specimen using a dual-signal HER2 gene assay (dual-probe ISH) HER2 testing (invasive component) by validated dual-probe ISH assay Batch controls and on-slide controls show appropriate hybridization HER2/CEP17ratio <2.0 Group 4 Average HER2copy number ≥4.0 and <6.0 signals/cell Press analysis: 4.1% of >10,000 patients. Generally IHC 0/1+. Patients in this category had similar DFS and OS without trastuzumab when compared with patients with ratio <2 and copy number <4 Additional work-up required Assess IHC using sections from the same tissue sample used for ISH DFS = disease-free survival; OS = overall survival. Press MF et al. J ClinOncol. 2016;34:3518-3528.

  9. San Antonio Breast Cancer Symposium, December 6, 2018 Equivocal HER2 Results PD3-05 ASCO-CAP FISH Groups: Comparison of HER2 Gene / CEP17 Status (FISH) with HER2 Protein Expression (IHC) ASCO 2013/14 guidelines recommend using chromosome 17p/q alternative control genomic sites (TP53, D17S122, SMS, RARA, TOP2A) to resolve equivocal cases CEP17 P-arm alternative control sites This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  10. San Antonio Breast Cancer Symposium, December 6, 2018 Equivocal HER2 Results PD3-05 Hypothesis • Alternative control loci show heterozygous deletion in a substantial proportion of breast cancers; • Use of these loci leads to false-positives; • HER2 FISH false-positive breast cancer patients same clinical outcomes as HER2-normal breast cancer; and • HER2-equivocal breast cancers seldom show HER2 protein overexpression (IHC 3+) This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  11. San Antonio Breast Cancer Symposium, December 6, 2018 Equivocal HER2 Results PD3-05 Hypothesis • Alternative control loci show heterozygous deletion in a substantial proportion of breast cancers; • Use of these loci leads to false-positives; • HER2 FISH false-positive breast cancer patients same clinical outcomes as HER2-normal breast cancer; and • HER2-equivocal breast cancers seldom show HER2 protein overexpression (IHC 3+) Methods • Retrospective analysis of alternative control sites in pts with data available through METABRIC (N=1980) or whose tissue available from BCIRG-005 study (N=3298). • HER2 IHC performed for HER2 protein expression This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  12. Chromosome 17 Regional Gene Copy Gains / Losses based on GISTIC among Alternative Control Genomic Sites Compared to HER2/ERBB2 Gene Copy Gains / Losses in the METABRIC Cohort (N = 1915) San Antonio Breast Cancer Symposium, December 6, 2018 *GISTIC, Genomic Identification of Significant Targets in Cancer, a tool to identify genes targeted by somatic copy-number alterations (SCNAs); note that a subset of cases was not evaluable by GISTIC, thus 1915 of 1980 cases are reported here. Press MF, et al. JAMA Oncology, 2018. This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  13. San Antonio Breast Cancer Symposium, December 6, 2018 Equivocal HER2 Results PD3-05 Evaluation of HER2-Equivocal and HER2-Not-Amplified Breast Cancers by FISH: Specimen Accountability Patients Screened in Central Lab by FISH N=10,468 HER2 Not Amplified N=6199 (59.2%) HER2 Amplified N=4269 (40.8%) BCIRG-007 N=263 BCIRG-005 N=3298 BCIRG-006 N=3222 Arm 1. AC-T N=1649 Arm 2. TAC N=1649 Arm 2. ACTH N=1074 Arm 3. TCH N=1075 Arm 1. AC-T N=1073 ASCO-CAP ISH Group 3. N=16 ASCO-CAP ISH Group 4. N=183 ASCO-CAP ISH Group 2. N=52 ASCO-CAP ISH Group 1. N=3,321 ASCO-CAP ISH Group 5. N=3,079 FISH-negative. N=100 “FISH-Equivocal”. N=100 This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  14. San Antonio Breast Cancer Symposium, December 6, 2018 Equivocal HER2 Results PD3-05 Assessment of Heterozygous Deletions by FISH using Pairwise Comparisons of Alternative Control Genes and the Frequency of HER2 / Alternative Control ratios >2.0 using these same Alternative Control Genes: ASCO-CAP Group 4 (HER2-Equivocal) and ASCO-CAP Group 5 (HER2-not-amplified) Breast Cancers This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  15. San Antonio Breast Cancer Symposium, December 6, 2018 Equivocal HER2 Results PD3-05 Correlation of HER2 Protein Status by IHC among BCIRG-005 Trial Breast Cancers determined to be “HER2-Positive” using Various Alternative Control Probes (SMS, D17S122 and TP53) among ASCO-CAP Group 4 (HER2 Equivocal) This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  16. San Antonio Breast Cancer Symposium, December 6, 2018 Equivocal HER2 Results PD3-05 Outcomes for ASCO-CAP Group 4 (HER2-Equivocal) and ASCO-CAP Group 5 (HER2-not-amplified) Breast Cancer Patients: DFS and OS. Disease-Free Survival of ASCO-CAP FISH Group 4 (HER2-Equivocal) Compared to ASCO-CAP FISH Group 5 (HER2-negative) Overall Survival of ASCO-CAP FISH Group 4 (HER2-Equivocal) Compared to ASCO-CAP FISH Group 5 (HER2-negative) This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  17. San Antonio Breast Cancer Symposium, December 6, 2018 Equivocal HER2 Results PD3-05 Overall Survival for ASCO-CAP Group 4 (HER2-Equivocal) Breast Cancer Patients by HER2 / Alternative Probe Ratios ASCO-CAP FISH Group 4 (HER2-Equivocal): OS for HER2 / SMS Ratios >2.0 versus Ratios <2.0 ASCO-CAP FISH Group 4 (HER2-Equivocal): OS for HER2 / D17S122 Ratios >2.0 versus Ratios <2.0 This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  18. San Antonio Breast Cancer Symposium, December 6, 2018 Takehome Message and Things to Consider Equivocal HER2 Results PD3-05 • Assessment of ASCO/CAP Group 4 (HER2/CEP17 ratio<2, HER2 copy number 4-6) by use of alternative probes leads to high rate of false positive HER2 status • These tumors lack HER2 overexpression • Patients in group 4 have similar DFS/OS to group 5 without trastuzumab and should be treated as HER2 normal • Outstanding Questions: • Are these data sufficient to omit use of trastuzumab in patients in group 4? YES! • What about Group 2 (HER2 ratio 2 or more, HER2 copy number <4) and Group 3 (HER2 ratio <2 and copy number >6) (frequency of each <1% per Press analysis JCO 2016) This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  19. Adjuvant T-DM1 KATHERINE (Geyer C, et al. Abs GS1-10)

  20. Neoadjuvant T-DM1/Pertuzumabinferior to TCHP in terms of pCR but safer pCR HR+: T-DM1/P: 38% TCHP: 46% pCR HR-: T-DM1/P: 55% TCHP: 71% Hurvitz SA et al. Lancet Oncol 2018;19:115-126

  21. KATHERINE ADJUVANT STUDY KATHERINE Study Design • cT1-4/N0-3/M0 at presentation (cT1a-b/N0 excluded) • Centrally confirmed HER2-positive breast cancer • Neoadjuvant therapy must have consisted of • Minimum of 6 cycles of chemotherapy • Minimum of 9 weeks of taxane • Anthracyclines and alkylating agents allowed • All chemotherapy prior to surgery • Minimum of 9 weeks of trastuzumab • Second HER2-targeted agent allowed • Residual invasive tumor in breast or axillary nodes • Randomization within 12 weeks of surgery T-DM1 3.6 mg/kg IV Q3W 14 cycles R1:1 Trastuzumab 6 mg/kg IV Q3W 14 cycles N=1486 Radiation and endocrine therapy per protocol and local guidelines • Stratification factors: • Clinical presentation: Inoperable (stage cT4 or cN2–3) vs operable (stages cT1-3N0-1) • Hormone receptor: ER or PR positive vs ER negative and PR negative/unknown • Preoperative therapy: Trastuzumab vs trastuzumab plus other HER2-targeted therapy • Pathological nodal status after neoadjuvant therapy: Positive vs negative/not done • Primary Endpoint: iDFS This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at cegeyer@vcu.edu for permission to reprint and/or distribute.

  22. Baseline Characteristics of ITT Population (1) ^Includes North, Central, and South American Indians. This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at cegeyer@vcu.edu for permission to reprint and/or distribute.

  23. Characteristics of ITT Population (2): Stratification Factors ^Non-pertuzumab HER2-targeted agents included: neratinib, dacomitinib, afatinib, lapatinib. *Not a stratification factor, included for informational purposes. This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at cegeyer@vcu.edu for permission to reprint and/or distribute.

  24. Invasive Disease-Free Survival Trastuzumab T-DM1 100 80 60 TrastuzumabT-DM1 (n=743)(n=743) Invasive Disease-Free Survival Rate (%) IDFS Events, no. (%) 165 (22.2) 91 (12.2) Unstratified HR=0.50 (95% CI, 0.39–0.64) 40 20 P<0.0001 3-year IDFS 77.0% 88.3% 0 0 6 12 18 24 30 36 42 48 54 60 Time (months) No. at Risk Trastuzumab T-DM1 676 635 594 555 501 342 220 119 38 4 743 This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at cegeyer@vcu.edu for permission to reprint and/or distribute. 743 707 681 658 633 561 409 255 142 44 4

  25. IDFS Subgroup Analysis (1) Trastuzumab (n=743) T-DM1 (n=743) Trastuzumab Better Total N 3-Year IDFS 3-Year IDFS Hazard Ratio 95% CI T-DM1 Better Group All Clinical stage at presentation Operable Inoperable Hormone receptor status Negative (ER negative and PgR negative/unknown) Positive (ER and/or PgR positive) Preoperative HER2-directed therapy Trastuzumab alone Trastuzumab plus additional HER2-directed agent(s) Pathological nodal status after preoperative therapy Node positive Node negative/not done Age group (years) <40 40–64 ≥65 Race^ White Asian American Indian or Alaska Native Black or African American 1486 1111 375 412 1074 1196 290 689 797 296 1064 126 1082 129 86 40 77.0 82.8 60.2 66.6 80.7 75.9 81.8 67.7 84.6 74.9 77.1 81.1 79.1 71.9 60.3 66.0 88.3 92.3 76.0 82.1 90.7 87.7 90.9 83.0 92.8 86.5 88.8 87.4 88.8 82.5 81.8 94.7 0.50 0.47 0.54 0.50 0.48 0.49 0.54 0.52 0.44 0.50 0.49 0.55 0.51 0.65 0.44 0.13 (0.39–0.64) (0.33–0.66) (0.37–0.80) (0.33–0.74) (0.35–0.67) (0.37–0.65) (0.27–1.06) (0.38–0.71) (0.28–0.68) (0.29–0.86) (0.36–0.67) (0.22–1.34) (0.37–0.69) (0.32–1.32) (0.18–1.03) (0.02–1.10) ^149 were of multiple races or unknown race. 0.20 0.50 1.00 2.00 5.00 This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at cegeyer@vcu.edu for permission to reprint and/or distribute.

  26. IDFS Subgroup Analysis (2) Trastuzumab (n=743) T-DM1 (n=743) Total N 3-Year IDFS 3-Year IDFS Hazard Ratio 95% CI T-DM1 Better Trastuzumab Better Group All Primary tumor stage (at definitive surgery) ypT0, ypT1a, ypT1b, ypT1mic, ypTis ypT1, ypT1c ypT2 ypT3 ypT4^ Regional lymph node stage (at definitive surgery) ypN0 ypN1 ypN2 ypN3 ypNX Residual disease ≤1 cm with negative axillarylymph nodes ypT1a, ypT1b or ypT1mic and ypN0 Central HER2 status by IHC* 0/1+ 2+ 3+ 1486 637 359 359 108 23 679 433 189 67 118 331 25 326 1132 77.0 83.6 75.9 74.3 61.1 30.0 83.9 75.8 58.2 40.6 88.7 85.3 83.9 80.9 75.7 88.3 88.3 91.9 88.3 79.8 70.0 91.9 88.9 81.1 52.0 98.1 90.0 100.0 84.7 89.0 0.50 0.66 0.34 0.50 0.40 0.29 0.46 0.49 0.43 0.71 0.17 0.60 <0.01 0.83 0.43 (0.39–0.64) (0.44–1.00) (0.19–0.62) (0.31–0.82) (0.18–0.88) (0.07–1.17) (0.30–0.73) (0.31–0.78) (0.24–0.77) (0.35–1.42) (0.02–1.38) (0.33–1.12) (0.00–NE) (0.50–1.38) (0.32–0.58) ^Includes all ypT4 and 1 patient with ypTX; *Three patients had “unknown” HER2 IHC status. 0.20 0.50 1.00 2.00 5.00 This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at cegeyer@vcu.edu for permission to reprint and/or distribute.

  27. First IDFS Events Trastuzumab CNS* (5.9) CNS* (4.3) 22.2 T-DM1 15.9 12.2 Patients (%) 10.5 11.6 4.6 4.6 1.3 1.1 0.4 0.4 0.3 ^Patients who experience additional IDFS event(s) within 61 days of their first IDFS event are reported in the category according to the following hierarchy: [1] Distant recurrence; [2] Locoregional recurrence; [3] Contralateral breast cancer; [4] Death without prior event. *CNS metastases as component of distant recurrence (isolated or with other sites). This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at cegeyer@vcu.edu for permission to reprint and/or distribute.

  28. Distant Recurrence Trastuzumab T-DM1 100 80 60 Distant Recurrence-Free Rate (%) TrastuzumabT-DM1 (n=743)(n=743) 40 Events, no. (%) 121 (16.3) 78 (10.5) Unstratified HR=0.60 (95% CI, 0.45–0.79) 20 3-year event-free rate 83.0% 89.7% 0 0 6 12 18 24 30 36 42 48 54 60 Time (months) No. at Risk Trastuzumab T-DM1 679 643 609 577 520 359 233 126 41 4 743 This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at cegeyer@vcu.edu for permission to reprint and/or distribute. 743 707 682 661 636 564 412 254 143 45 4

  29. Overall Survival 100 80 Trastuzumab T-DM1 60 Survival (%) TrastuzumabT-DM1 (n=743)(n=743) 40 Events, no. (%) 56 (7.5) 42 (5.7) Unstratified HR=0.70 (95% CI, 0.47–1.05) P=0.0848 20 Boundary forstatistical significance HR<0.43 or P<0.000032 0 0 6 12 18 24 30 36 42 48 54 60 Time (months) No. at Risk Trastuzumab T-DM1 695 677 657 635 608 471 312 175 71 8 743 This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at cegeyer@vcu.edu for permission to reprint and/or distribute. 743 719 702 693 668 648 508 345 195 76 12

  30. Safety Overview ^Fatal AE was intracranial hemorrhage diagnosed after a fall with platelet count of 55,000. This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at cegeyer@vcu.edu for permission to reprint and/or distribute.

  31. AEs Leading to Treatment Discontinuation (≥1% Incidence Either Arm) This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at cegeyer@vcu.edu for permission to reprint and/or distribute.

  32. HER2+ Adjuvant Studies Von Minckwitz et al. N Engl J Med 2017;377

  33. Natural History of trastuzumab-treated curable HER2+ Disease Late Relapse by HR status in NCCTG N9831 + NSABP B31 Chumsri S et al CNS as 1st site of relapse in BCIRG-006 Chan A et al

  34. San Antonio Breast Cancer Symposium, December 6, 2018 Trastuzumab benefits hormone receptor positive & negative disease similarly • Oxford Overview:3 Steady recurrences seen years 5-20 in HR+ disease irrespective of HER2 status. • Objective: Using samples from N9831/B31, evaluate RFS with/without trastuzumab by HR status Slamon DJ et al. NEJM 2011. 2. Perez E et al. J Clin Oncol 2014:32. 3. Pan H et al. N Engl J Med 3017:377

  35. Late Relapse by HR status N9831/B31 (PD3-02) San Antonio Breast Cancer Symposium, December 4-8, 2018 RFS by HR Status and Treatment • Takehome: • HR+ disease does better than HR- regardless of treatment • Trastuzumab-treated HR+ disease does the best Trastuzumab HR+ Trastuzumab HR- Chemo HR+ Chemo HR- This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  36. Late Relapse by HR status N9831/B31 (PD3-02) San Antonio Breast Cancer Symposium, December 4-8, 2018 Annualized Hazard Rates for Relapse or Death by HR Status Chemotherapy Alone Trastuzumab HR+ HER2- This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  37. Late Relapse by HR status N9831/B31 (PD3-02) San Antonio Breast Cancer Symposium, December 4-8, 2018 Cumulative Probability (%) of Relapse or Death by Hormone Receptor and Nodal Status *Only in NCCTG N9831**Estimated based on patients who survived 5 years without relapse. ***Pan et al. N Engl J Med. 2017 Nov 9;377(19):1836-1846 This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  38. Late Relapse by HR status N9831/B31 (PD3-02) Takehome and Things to Consider • Similar to triple negative breast cancer, HR negative HER2+ breast cancer has higher risk of relapse in first 5 years and then that difference disappears • For HR+ HER2+ breast cancer, low cumulative hazard rate of recurrence between years 5-10 • N0 3.23% • N1 6.39% • Calls into question the benefit, if any, of extended endocrine therapy, use of pertuzumab and/or use of neratinib in N0 and N1 disease

  39. San Antonio Breast Cancer Symposium, December 6, 2018 Natural History of HER2+ Disease Late Relapse by HR status in NCCTG N9831 + NSABP B31 Chumsri S et al CNS as 1st site of relapse in BCIRG-006 Chan A et al This presentation is the intellectual property of the author/presenter. Contact them at shurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  40. San Antonio Breast Cancer Symposium, December 6, 2018 CNS Relapse BCIRG-006 (PD3-06) • 10%-30% of pts with early stage BC will ultimately develop a CNS relapse - HER2 overexpression predicts CNS relapse • Rates of CNS metastasis as first site of relapse in adjuvant studies in HER2+ trastuzumab-treated patients: • Joint Analysis (B31-N9831): 33/1672 (1.9%) • HERA: 37/1703 (2.1%) developed CNS • Adjuvant trastuzumab has increased DFS and OS (but does not penetrate the blood-brain barrier), leading to a relative increase in the frequency of brain metastases in the this population in comparison to the pre-trastuzumab era. • Objective: Using data from BCIRG-006 adjuvant tratstuzumab study, evaluate frequency of CNS as 1st site of relapse and estimate DFS/OS of these pts Lin NU et al J Clin Oncol 22:3608–3617, 2004; Kennecke H et al J Clin Oncol 28:3271–3277, 2010 This presentation is the intellectual property of the author/presenter. Contact them at shurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  41. CNS Relapse BCIRG-006 (PD3-06) San Antonio Breast Cancer Symposium, December 6, 2018 • Median follow-up 10.3 years, 575 (18%) had distant relapse • 101/575 CNS first site of recurrence • 74/101 (73%) CNS only site of relapse This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  42. CNS Relapse BCIRG-006 (PD3-06) San Antonio Breast Cancer Symposium, December 6, 2018 Year of follow-up # of CNS relapses This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  43. San Antonio Breast Cancer Symposium, December 6, 2018 CNS Relapse BCIRG-006 (PD3-06) Univariate and multivariate analyses for DFS This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  44. CNS Relapse BCIRG-006 (PD3-06) Takehome & Things to Consider San Antonio Breast Cancer Symposium, December 6, 2018 • With over 10 years follow up, 3.1% of patients develop CNS metastases as first site of relapse, the majority of whom have no extracranial disease • CNS metastases rates were similar among the 3 arms as were long term outcomes • Risk highest in first 3 years, though recurrences observed out to 10 years • Risk highest in ER- or >4 nodes This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  45. CNS Relapse BCIRG-006 (PD3-06) Takehome & Things to Consider San Antonio Breast Cancer Symposium, December 6, 2018 • With over 10 years follow up, 3.1% of patients develop CNS metastases as first site of relapse, the majority of whom have no extracranial disease • CNS metastases rates were similar among the 3 arms as were long term outcomes • Risk highest in first 3 years, though recurrences observed out to 10 years • Risk highest in ER- or >4 nodes • Need for trials evaluating use of CNS penetrating agents (neratinib, tucatinib) in ER- 4+ LN+ disease • Should we be evaluating surveillance brain imaging first 3 years in the highest risk patients? This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  46. San Antonio Breast Cancer Symposium, December 6, 2018 Novel Therapies: PATRICIA: Palbociclib/trastuzumab Ciruelos E et al KATE-2: T-DM1 +/- atezolizumab Emens L et al This presentation is the intellectual property of the author/presenter. Contact them at shurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  47. PATRICIA Palbociclib/Trastuzumab (PD3-03) San Antonio Breast Cancer Symposium, December 6, 2018 For Stage I to be successful, at least 6 patients of 15 had to be progression-free at 6 months (PFS6R of 40%) in each cohort. This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  48. PATRICIA Palbociclib/Trastuzumab (PD3-03) San Antonio Breast Cancer Symposium, December 6, 2018 Safety/ Efficacy PAM50 N=15 N=14 N=15 N=26 N=15 This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  49. PATRICIA Palbociclib/Trastuzumab (PD3-03) San Antonio Breast Cancer Symposium, December 6, 2018 More heavily pretreated patients than included in phase III RCT of CDK4/6i Grade 3/4 Adverse Events This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

  50. PATRICIA Palbociclib/Trastuzumab (PD3-03) San Antonio Breast Cancer Symposium, December 6, 2018 PFS for each arm A PFS-6 mos B For part 1 to be successful, at least 6 patients of 15 had to be progression-free at 6 months (PFS6R of 40%) in each cohort. Only HR+ cohorts met this. This presentation is the intellectual property of the author/presenter. Contact them atshurvitz@mednet.ucla.edufor permission to reprint and/or distribute

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