WAHO Best of SABCS: - Survivorship - Prevention - Maintenance. - Prediction - Tiny bit of prevention

Transcription

1 WAHO Best of SABCS: - Survivorship - Prevention - Maintenance Amye Tevaarwerk, MD Associate Professor Hematology & Oncology University of Wisconsin Carbone Cancer Center - Prediction - Tiny bit of prevention January 27 th, 2018

2 Disclosures & Slides None Slides used with permission from: 1. D. Hershman 2. W. Janni 3. R. Coombes 4. D. Yee 5. R. Chlebowski 6. I. Sestak blah

3 Outline Symptom management qgs4-04. Randomized blinded sham- and waitlist-controlled trial of acupuncture for joint symptoms related to aromatase inhibitors in women with early stage breast cancer (S1200) Treatment in the Maintenance or Survivorship Phase qgs1-06. Extended adjuvant bisphosphonate treatment over five years in early breast cancer does not improve disease-free and overall survival compared to two years of treatment qgs3-03. A phase III multicentre double blind randomised trial of celecoxib versus placebo in primary breast cancer patients (REACT - Randomised EuropeAn Celecoxib Trial) Predicting Outcomes qgs3-08. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL qgs5-07. Weight change in postmenopausal women and breast cancer risk in the Women's Health Initiative Observational study qgs6-01. Integration of clinical variables for the prediction of late distant recurrence in patients with oestrogen receptor positive breast cancer treated with 5 years of endocrine therapy...

4 GS4-04 Randomized Blinded Sham- and Waitlist- Controlled Trial of Acupuncture for Joint Symptoms Related to Aromatase Inhibitors in Women with Early Stage Breast Cancer (SWOG 1200) Dawn L. Hershman, Joseph M. Unger, Heather Greenlee, Jillian Capodice, Danika L. Lew, Amy Darke, Alice Kengla, Marianne K. Melnik, Carla W. Jorgensen, William H. Kreisle, Lori M. Minasian, Michael J. Fisch, N. Lynn Henry, Katherine D. Crew

5 Clinical Concern, Trial Design Despite the efficacy of aromatase inhibitors, many patients suffer from joint side effects => non-compliance? Compliance to AI s is associated with improved disease-free survival. Acupuncture is a popular non-pharmacologic modality for the treatment of a variety of medical conditions. Several small studies have suggested acupuncture may be beneficial for AI-arthralgias; however others have shown no benefit. The overall interpretation of these trials has been uncertain due to short duration, small sample sizes and differences in methodology. PRIMARY ENDPOINT Hershman, DL. JCO,2008 Chrigwin. JH. JCO, 2016 Crew, KD. JCO, 2010 True Acupuncture 2x week x 6 weeks True Acupuncture 1x week x 6 weeks No Acupuncture 12 weeks AI > 3/10 Worst Pain N=226 Sham Acupuncture 2x week x 6 weeks Sham Acupuncture 1x week x 6 weeks No Acupuncture 12 weeks Assessment Week Wait List Control 6 weeks Wait List Control 6 weeks Wait List Control 12 weeks

6 Primary Endpoints, Eligibility Primary outcome measure = brief pain inventory (BPI) worst pain score at 6 weeks. Hypothesis = true acupuncture would decrease worst pain compared to both sham acupuncture or wait list control. alpha=.025 two-sided test to account for two independent comparison. Analysis used all evaluable, randomized patients under the intention-to-treat principle. Stage 1-3 hormone sensitive breast cancer Third-generation AI for at least 30 days prior to registration Score of >3 (range, 0-10) on the worst pain item of the BPI, Symptoms started or increased since starting AI No opioids or corticosteroid and no alternative/physical therapy for the treatment of joint pain within 28 days prior to registration No prior acupuncture treatment for joint symptoms at any time, but allowed for other reasons >12 months prior

7 Intervention: 3 groups True Acupuncture Standard Traditional Chinese Medicine point prescription to reduce pain and decrease stress (30-45 min per session), protocol tailored to the most painful joints with extensive training.. Sham Acupuncture Shallow needle insertion utilizing thin and short needles at non-acupuncture points Wait List Control True acupuncture offered after 24 weeks 226 PATIENTS RANDOMIZED Crew, KD. JCO,2010 True Acupuncture N=110 Sham Acupuncture N=59 Waitlist Control N=57 Inevaluable (10) no baseline BPI measure 1 no 6 week BPI measure 9 Inevaluable (5) no baseline BPI measure 5 Inevaluable (6) no baseline BPI measure 1 no 6 week BPI measure 5 Primary analysis at 6 weeks: n=100 Analysis at 12 weeks: n=101 Analysis at 24 weeks: n=97 Primary analysis at 6 weeks: n=54 Analysis at 12 weeks: n=54 Analysis at 24 weeks: n=54 Primary analysis at 6 weeks: n=51 Analysis at 12 weeks: n=51 Analysis at 24 weeks: n=50

8 PATIENT CHARACTERISTICS Age, years Total (n=226) True Acupuncture (n=110) Sham Acupuncture (n=59) Median Waitlist Control (n=57) Hispanic, N (%) 21 7% 11 10% 7 12% 3 5% Race, N (%) White % 88 83% 54 93% 51 91% Black 10 5% 6 6% 2 3% 2 4% Asian 15 7% 11 10% 2 3% 2 4% Prior Chemotherapy, N (%) San Antonio Breast Cancer Symposium, December 5-9, % 56 51% 31 53% 24 42% AI Therapy (median yrs) Prior Acupuncture, N (%) 44 19% 19 17% 13 22% 12 21% Baseline Score BPI WP

9 6-WEEK RESULTS - WORST PAIN (BPI) Percent with 2-point change WORST PAIN Fitted Difference* P-value True v. Sham 0.92 ( ).01 True v. Waitlist 0.96 ( ).01 Percent 2-point change P<0.009 P<0.004 Sham v. Waitlist 0.05 ( ).92 * Corrected for baseline score and study site

10 Linear Mixed Model - Worst Pain (BPI)

11 RESULTS - Other 6 Week Endpoints BPI AVERAGE PAIN Fitted Difference P-value True v. Sham 0.60 (0.03, 1.17).04 True v. Waitlist 0.71 (0.15, 1.28).01 Sham v. Waitlist 0.08 (-0.51, 0.68).79 BPI STIFFNESS Fitted Difference P-value True v. Sham 1.00 (0.19, 1.81).02 True v. Waitlist 1.09 (0.26, 1.92).01 Sham v. Waitlist 0.17 (-0.62, 0.96).67 WOMAC Fitted Difference P-value True v. Sham 9.27 (3.73, 14.82).001 True v. Waitlist (6.76, 17.59) <.0001 Sham v. Waitlist 3.01 (-2.75, 8.78) 0.31 M-SACRAH Fitted Difference P-value True v. Sham 6.23 (0.92, 11.55).02 True v. Waitlist 9.40 (4.52, 14.28).0002 Sham v. Waitlist 4.26 (-1.32, 9.84).14

12 Linear Mixed Model: Other Endpoints This presentation is the intellectual property of the presenter. Contact her at for permission to reprint and/or distribute.

13 San Antonio Breast Cancer Symposium, December 5-9, 2017 Linear Mixed Model: Other Endpoints This presentation is the intellectual property of the presenter. Contact her at for permission to reprint and/or distribute.

14 ADVERSE EVENTS True Acupuncture (n=106) Grade Sham Acupuncture (n=55) Grade ADVERSE EVENTS Bruising Dizziness Ear pain Hematoma Bleeding at injection site Pain in extremity Presyncope Grade 1 bruising (47% vs. 25%) p=.01 Patients on true acupuncture were more likely to believe they were receiving true acupuncture 6 weeks (68% vs. 36%, p<.0001). The intervention effect did not differ between those believing vs. not believing they were receiving true acupuncture at either 6 weeks (p=.16) using interaction tests.

15 CONCLUSIONS from study team: We have shown consistently, with multiple measures assessing pain and stiffness, that true acupuncture generated better outcomes than either control group in a large multicenter randomized controlled trial. Transitioning from twice-a-week to once-a-week acupuncture maintained the effect of the intervention. The intervention effects persisted 12 weeks following completion of the intervention. The toxicity of the intervention was minimal and limited to grade 1 bruising.

16 Considerations for clinical practice: Is all accupuncture the same? Accupuncture vs duloxetine vs switching strategies? Acupuncture provides a non-pharmacologic option that may improve symptoms and possibly increase AI adherence? Need for subsequent outcome studies For patients reluctant to take a prescription medication, acupuncture may be good alternative Do we need studies of combinations? Is there an optimal strategy? The cost of the 12-week (18 session) intervention was ~ $1,250 ($65- $75/session) Insurance Coverage?

17 GS1-06 Extended adjuvant bisphosphonate treatment over five years in early breast cancer does not improve disease-free and overall survival compared to two years of treatment: Phase III data from the SUCCESS A study Wolfgang Janni, Thomas WP Friedl, Tanja Fehm, Volkmar Mueller, Werner Lichtenegger, Jens Blohmer, Ralf Lorenz, Helmut Forstbauer, Emanuel Bauer, Visnja Fink, Inga Bekes, Jens Huober, Julia Jückstock, Andreas Schneeweiss, Hans Tesch, Sven Mahner, Sara Y Brucker, Georg Heinrich, Lothar Häberle, Peter A. Fasching, Matthias W Beckmann, Robert Coleman, Brigitte Rack

18 Background: Bisphosphonates Bisphosphonates prevent the loss of bone density and have been shown to reduce skeletal-related events in cancer patients Adjuvant bisphosphonate treatment in early breast cancer patients leads to improved breast cancer survival and reduced rate of breast cancer recurrences in the bone, especially in postmenopausal patients 1 Both European and North American guidelines: adjuvant bisphosphonates should be offered to postmenopausal women as part of their adjuvant systemic treatment However, optimal treatment duration is unclear 1 Early Breast Cancer Trialists Collaborative Group (EBCTCG). Lancet Oncol. 2015; 386:

19 SUCCESS A: open-label, multicenter, 2x2 factorial design, randomized controlled Phase III study) 5- FU 500 mg/m 2, Epirubicin 100 mg/m 2, Cyclophosphamide 500 mg/m 2 q3w Docetaxel 100 mg/m 2 q3w Endocrine treatment: Docetaxel 75 mg/m 2, Gemcitabine mg/m 2 d1,8 q3w before chemotherapy after chemotherapy after 2 years after 5 years Blood sampling for CTC assessment First randomization: 3 cycles FEC100 followed by 3 cycles docetaxel vs. 3 cycles FEC100 followed by 3 cycles docetaxel plus gemcitabine Second randomization: 5 years vs. 2 years of zoledronate (4 mg i.v. every 3 months for 2 years, followed by 4 mg i.v. every 6 months for 3 years vs. 4 mg i.v. every 3 months for 2 years) Tamoxifen 20 mg qid p.o. x 2a (plus Goserelin 3.6 mg depot x 2a in premenopausal pts Anastrozole 1 mg qid p.o. x 3a in postmenopausal pts (Tam in premenopausal pts)

20 Patient characteristics (n = 2987) Patient and tumor characteristics* Tumor size Nodal stage Histological grading Histological type Hormone receptor status HER2 status Menopausal status Type of surgery Adjuvant chemotherapy 5 years of zoledronate 2 years of zoledronate n % n % pt1/pt pt3/pt pn pn G G G ductal other negative positive negative positive premenopausal postmenopausal breast conserving mastectomy FEC-DocG FEC-Doc Patients in the two randomization arms well balanced with regard to clinicopathological characteristics (all p > 0.05) * missing data in some categories

21 Adapted disease-free survival (DFS) and overall survival (OS) by zoledronate treatment arm

22 Bone recurrences by zoledronate treatment arm (as of 2 years after the start of zoledronate treatment) Bone recurrences as first distant recurrence* 5 years of zoledronate: 25 events 2 years of zoledronate: 28 events * with or without concurrent other recurrence

23 Subgroups adapted DFS by menopausal status premenopausal postmenopausal

24 Subgroups adapted OS by menopausal status premenopausal postmenopausal

25 Conclusion by the study team: At this early time point, our study showed no difference in DFS or OS between 5-years and 2- years of adjuvant zoledronate treatment following adjuvant chemotherapy in high-risk early breast cancer patients, irrespectively of menopausal status 5 years of adjuvant zoledronate treatment should not be considered currently in these patients in the absence of decreased bone density

26 Considerations for clinical practice: Early time point: 50 months Different schedule of ZA than current suggested by ASCO-endorsed guidelines SUCCESS: 4 mg every 3 months in first 2 yrs ASCO endorsed: 4 mg every 6 months for 3-5 yrs My thoughts: IF doing adjuvant ZA, may support choosing the shortage duration

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44 Thoughts. Ongoing interest in anti-inflammatories in cancer Currently, aspirin vs placebo study ongoing in the adjuvant Breast Cancer setting No clear signal that this trial should not continue forward But also no strong argument can be made for recommending this category of drugs off-study in the absence of other reasons blah

45 Switching to prediction Less what to do in clinic

46 Pathological Complete Response Predicts Event- Free and Distant Disease Free Survival in the I-SPY 2 TRIAL Douglas Yee, MD Masonic Cancer Center, University of Minnesota On behalf of I-SPY2 Investigators and authors: Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS, Hylton NM, Forero-Torres A, van't Veer LJ, Perlmutter J, Rugo HS, Melisko M, Chen Y-Y, Balassanian R, Krings G, Datnow B, Hasteh F, Tipps A, Weidner N, Zhang H, Tickman R, Thornton S, Ritter J, Amin K, Klein M, Chen B, Keeney G, Ocal T, Feldman M, Klipfel N, Sattar H, Mueller J, Gwin K, Baker G, Kallakury B, Zeck J, Duan X, Ersahin C, Gamez R, Troxell M, Mansoor A, Grasso LeBeau L, Sams S, Wisell J, Wei S, Harada S, Vinh T, Stamatakos MD, Tawfik O, Fan F, Adams A, Rendi M, Minton S, Magliocco A, Sahoo S, Fang Y, Hirst G, Singhrao R, Asare SM, Wallace AM, Chien AJ, Ellis ED, Han HS, Clark AS, Boughey JC, Elias AD, Nanda R, Korde L, Murthy R, Lang J, Northfelt D, Khan Q, Edmiston KK, Viscusi R, Haley B, Kemmer K, Zelnak A, Berry DA, Esserman LJ.

47 BACKGROUND pcr and EFS FDA Meta Analysis (Cortazar et al, Lancet 2014) >11K patients from 12 neoadjuvant trials Median follow-up for EFS: 5.4 years

48 I-SPY2 TRIAL San Antonio Breast Cancer Symposium, Dec 5-9, 2017 Study Design of I-SPY2 T0 T1 T2 T3 TS Paclitaxel* (control arm) 12 weekly cycles Anthracycline (AC) 4 cycles pcr SCREEN ADAPTIVE RANDOMIZATION AGENT 1 ± Paclitaxel* 12 weekly cycles Anthracycline (AC) 4 cycles RC MRI Biopsy Blood Draw AGENT 5 ± Paclitaxel* 12 weekly cycles Anthracycline (AC) 4 cycles HR+/HER2- patients with low-risk MammaPrint Scores are not enrolled in I-SPY2

49 I-SPY2 TRIAL San Antonio Breast Cancer Symposium, Dec 5-9, 2017 Analysis Primary Endpoint: Pathological complete response (pcr) Defined as no residual invasive cancer in breast or lymph nodes Assessed using the Residual Cancer Burden (RCB) method* Highly reproducible between local and central pathologist review Scatterplot of RCB index entered by Site vs. Central Review Intent-to-treat: Patients who did not complete assigned therapy are considered non-pcr (withdrew, left the institution, received non-protocol therapy, or progressed). Secondary endpoints: RCB EFS I-SPY 2 To Date >1000 patients completed surgery 11 investigational agents/combinations *Symmans, et al. J Clin Oncol 25: PMID:

50 I-SPY2 TRIAL San Antonio Breast Cancer Symposium, Dec 5-9, 2017 EFS Dataset Evaluable population: (35%) pcr 487 (65%) non-pcr Median follow-up: 2.7 yrs ( ) 126 EFS events 109 DRFS events 12 patients did not go to surgery considered non-pcr per protocol pcr distribution by subtype 50

51 I-SPY2 TRIAL San Antonio Breast Cancer Symposium, Dec 5-9, 2017 pcr is a highly significant predictor of EFS and DRFS EFS OVERALL DRFS 51

52 I-SPY2 TRIAL San Antonio Breast Cancer Symposium, Dec 5-9, 2017 pcr is predictive of EFS and DRFS in TNBC EFS DRFS 52

53 I-SPY2 TRIAL San Antonio Breast Cancer Symposium, Dec 5-9, 2017 pcr is predictive of EFS and DRFS in HR+/HER2 EFS DRFS 53

54 I-SPY2 TRIAL San Antonio Breast Cancer Symposium, Dec 5-9, 2017 pcr is predictive of EFS and DRFS in HR /HER2+ EFS HR-HER2+ DRFS 54

55 pcr is predictive of EFS and DRFS in HR+/HER2+ EFS HR+HER2+ DRFS 55

56 EFS by pcr & non-pcr by Subtype

57 EFS and DRFS Hazard Ratio for pcr vs non-pcr EFS DRF S

58 I-SPY2 EFS Hazard Ratio for pcr/non-pcr compared to FDA meta-analysis and cooperative group results I-SPY 2 Cortazar Metaanalysis Overall 0.20 ( ) 0.48 ( ) Cooperative Group CALGB *HR+HER ( ) 0.49 ( ) HER ( ) 0.39 ( ) HR-HER ( ) 0.24 ( ) 0.30 ( ) *Mammaprint low patients excluded

59 Summary per authors pcr is a strong predictor of EFS and DRFS in the setting of a multiple agent platform trial that includes: Standards for eligibility high risk for early recurrence (MP low risk, HR+Her2- excluded) exclusion of metastatic disease All chemotherapy given before pcr determination Standards for pathology assessment and multidisciplinary identification (surgeons, radiologists, pathologists) Long term follow-up of patients over time (correlation of early, intermediate, and late endpoints) pcr is equally predictive across all tumor subsets pcr as an endpoint enables rapid evaluation of novel therapy combinations and can accelerate the identification of effective and potentially less toxic regimens

60 The Future of I-SPY 2 Achieving pcr through any therapy for any subtype is a sufficient endpoint Develop minimally invasive techniques (MRI and biopsy) to identify pcr prior to definitive surgery Validate robust MRI and tissue predictors of pcr Deescalate toxic therapy (AC) if pcr obtained early Re-assign patients to new therapies if pcr is not predicted Validate robust MRI and tissue predictors of non-pcr Assign new therapies based on molecular profiling of tumor and link to investigational agents

61 Thoughts In some groups without pcr, women still did well HR+ HER2+ HR+ HER2- Followup is still pretty short for HR+ What tempers the risk if pcr not obtained? How were the HER2+ patients treated? blah

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77 GS6-01 Integration of clinical variables for the prediction of late distant recurrence in patients with estrogen receptor positive breast cancer treated with 5 years of endocrine therapy Ivana Sestak 1 Meredith M. Regan 2, Andrew Dodson 3, Giuseppe Viale 4, Beat Thürlimann 5, Marco Colleoni 6, Jack Cuzick 1, Mitch Dowsett 3 1. Centre for Cancer Prevention, Queen Mary University of London, London, United Kingdom 2. Dana Farber Cancer Institute, Boston, United States 3. Ralph Lauren Centre for Breast Cancer Research, Royal Marsden, London, United Kingdom 4. European Institute of Oncology & University of Milan, Milan, Italy 5. Kantonsspital St. Gallen, St. Gallen, Switzerland 6. European Institute of Oncology, Milan, Italy

78 Background More than 80% of breast cancer patients present with ERpositive disease for whom 5+ years of adjuvant endocrine therapy is standard Breast cancer recurrences continue to occur in about 50% Risks range from 10 to 40% depending on nodal status, tumor size, and grade 3(Pan et al., 2017, NEJM) Extended endocrine therapy can reduce risk of recurrence but depends on an assessment of potential side effects and benefits (Davies et al., 2013, Lancet; Gray et al., 2013, JCO; Goss et al., 2016, NEJM Prediction of late distant recurrence is an important clinical question in women who are recurrence-free after 5 years of endocrine therapy Clinicopathological parameters are routinely used to estimate risk of breast cancer recurrence Nodal status most powerful prognostic marker for late recurrence (?)

79 Aims 1. To develop a prognostic tool (CTS5) specifically for prediction of late distant recurrence using clinicopathological parameters 2. To compare prognostic performance of CTS5 to published Clinical Treatment Score (CTS0) CTS0 developed in TransATAC (N=1125) in presence of IHC markers and in chemotherapy untreated women (Cuzick et al., 2011, JCO)

80 Statistical analysis Postmenopausal women with ER-positive breast cancer who were distant recurrence free after 5 years of ET Chemotherapy treated and untreated Primary endpoint: Distant recurrence (DR) after 5 years of ET Cox regression models used to determine prognostic value HRs for a change in one SD Kaplan-Meier method used for risk estimates Cut-off points for risk groups: Low < 5% DR risk in years 5-10 Intermediate 5-10% DR risk in years 5-10 High > 10% DR risk in years 5-10

81 Training/validation cohorts Clinical variables not accessible N=55 ATAC N=5216 Median FUP: 9.8 years BIG1-98 N=8010 Median FUP: 8.1 years Clinical variables not accessible N=281 Censored/had distant recurrence within first 5 years N=426 Evaluable clinical variables N=5161 Evaluable clinical variables N=7729 Censored/had distant recurrence within first 5 years N=1018 Evaluable clinical variables and distant recurrence-free at 5 years N=4735 Evaluable clinical variables and distant recurrence-free at 5 years N=6711

82 Patient characteristics ATAC (N=4735) BIG 1-98 (N=6711) Age (years), median (IQR) 64 (57-71) 61 (56-67) Nodal involvement Negative 68.0% 60.9% % 29.0% % 10.1% Grade Well 24.3% 22.7% Intermediate 50.4% 57.0% Poor 25.3% 20.3% Tumour size <10mm 19.7% 17.5% 10-20mm 49.8% 47.8% >20mm 32.0% 34.8% Chemotherapy 19.5% 24.2% Endocrine therapy Tamoxifen 5 years 50.1% 29.6% Anastrozole or Letrozole 5 years 49.9% 30.4% 2 years Letrozole/3 Years Tamoxifen % 2 years Tamoxifen/3Years Letrozole % Distant recurrence (>5 years) 7.0% 5.5%

83 CTS5 score development Univariate Cox regression to determine prognostic value of each variable: Clinical variable HR (95% CI) P-value Number of positive nodes 1.14 ( ) < Tumor size (mm) 1.10 ( ) < Grade (1 vs. 2, 1 vs. 3) 2.26 ( ) / 3.37 (2.33- < / < ) Age (years) 1.04 ( ) < Endocrine therapy (T vs. A) 0.84 ( ) Final CTS5 model: Node: 0 = Negative 1 = 1 positive 2 = 2-3 positive 3 = 4-9 positive 4 = >9 positive Size: Continuous (if >30 then = 30) Grade: 0 = Grade 1 1 = Grade 2 2 = Grade 3 Age: Continuous

84 DR free (%) in years 5-10 Distant recurrence free since randomization (%) Low ATAC (training) HR (95% CI) Reference Intermediate 3.42 ( ) High 9.43 ( ) Low: N=1989 (42.0%) Intermediate: N=1484 (31.3%) High: N=1262 (26.7%) 5-10 year DR risk (%) 2.5% ( ) 7.7% ( ) 20.3% ( ) Distant recurrence free since randomization (%) Low BIG 1-98 (validation) HR (95% CI) Reference Intermediate 2.19 ( ) High 5.33 ( ) Low: N=2861 (42.6%) Intermediate: N=2136 (31.8%) High: N=1714 (25.5%) 5-10 year DR risk (%) 3.6% ( ) 6.9% ( ) 17.3% ( ) Follow-up time since randomization [years] Follow-up time since randomization [years] This presentation is the intellectual property of the author/presenter. Contact i.sestak@qmul.ac.uk for permission to reprint and/or distribute.

85 Combined dataset: DR free (%) Distant recurrence free since randomization (%) Low Low: N=4885 (42.7%) Intermediate: N=3698 (32.3%) High: N=2863 (25.0%) All patients N=11446 HR (95% CI) Reference Intermediate 2.77 ( ) High 7.36 ( ) 5-10 year DR risk (%) 3.0% ( ) 7.3% ( ) 18.9% ( ) Follow-up time since randomization [years]

86 Combined dataset: DR free (%) Node-negative N=7309 Distant recurrence free since randomization (%) Low Low: N=4431 (60.6%) Intermediate: N=2509 (34.3%) High: N=369 (5.1%) HR (95% CI) Reference Intermediate 2.67 ( ) High 4.22 ( ) 5-10 year DR risk (%) 2.7% ( ) 7.2% ( ) 10.4% ( ) Follow-up time [years] 9 10

87 Combined dataset: DR free (%) Distant recurrence free since randomization (%) (95% CI) Low Node-negative N=7309 Low: N=4431 (60.6%) Intermediate: N=2509 (34.3%) High: N=369 (5.1%) HR Reference Intermediate 2.67 ( ) High 4.22 ( ) 5-10 year DR risk (%) 2.7% ( ) 7.2% ( ) 10.4% ( ) Distant recurrence free since randomization (%) (95% CI) Low 1-3 positive nodes N=3110 Low: N=453 (14.6%) Intermediate: N=1145 (36.8%) High: N=1512 (48.6%) HR Reference Intermediate 3.40 ( ) High 6.54 ( ) 5-10 year DR risk (%) 2.9% ( ) 8.2% ( ) 14.9% ( Follow-up time [years] Follow-up time [years]

88 Combined dataset: risk curve 5-10 years risk of DR since randomization (%) Low Intermediate High CTS year DR risk (%) CTS

89 San Antonio Breast Cancer Symposium December 5-9, 2017 Combined dataset: risk curve 5-10 year DR risk (%) CTS years risk of DR since randomization (%) % Low Intermediate High CTS This presentation is the intellectual property of the author/presenter. Contact i.sestak@qmul.ac.uk for permission to reprint and/or distribute.

90 Conclusions CTS5 was highly prognostic for prediction of late DR Large proportion of women (42%) identified where value of extended endocrine therapy is limited CTS5 more accurate for late DR than CTS0 (Cuzick et al., 2011, JCO) Strengths: Large clinical trial data with long-term follow-up Clinico-pathological parameters measured in all patients Limitations: Only applicable to postmenopausal women Both trials before routine HER2 testing and directed therapy ècts5 simple tool to calculate risk of late distant recurrence

91 Thoughts. Post-menopausal only Datasets don t reflect modern practices with HER2 etc Prognostic, not predictive Not yet published. blah

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95 I-SPY2 TRIAL San Antonio Breast Cancer Symposium, Dec 5-9, 2017 Agent Timeline n=69 11 Agent Combinations Included in this analysis, including control 95