2 nd annual San Antonio breast cancer symposium review january 28, 2012

1. 2nd annual San Antonio breast cancer symposium reviewjanuary 28, 2012 Sponsored By:

2. 35th Annual San Antonio Breast Cancer Symposium: Radiation Oncology Update Welela Tereffe, M.D., M.P.H. Department of Radiation Oncology M. D. Anderson Cancer Center Houston, TX

3. Partial breast brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole breast irradiation in older patientsSmith GL et. al. (abstract S2-1)

4. Partial Breast Irradiation: Patterns of Care • Breast brachytherapy after lumpectomy has emerged as a popular treatment for early breast cancer • Multiple studies document steady rise in use across the US • Ten percent of older patients are now treated with breast brachytherapy, compared with <1% a decade ago

5. Brachytherapyvs. Whole Breast Irradiation Breast brachytherapy: • Delivers radiation through catheter(s) • Requires 1 week of treatment (vs. 3 to 7 weeks) Courtesy of Dr. Grace Smith

6. Need For More Data • Randomized trials prove effectiveness of WBI for decreasing recurrences compared with lumpectomy alone • Randomized comparison of brachytherapy vs. WBI yet to mature • Non-randomized comparison may help ongoing treatment decisions Courtesy of Dr. Grace Smith

7. Brachytherapy vs. WBI: Study Cohort • Medicare claims-based analysis • 130,535 women • Age ≥ 67 years • Incident invasive breast cancer diagnosed between 2000 and 2007 • Treated with lumpectomy • Followed by radiation treatment • WBI • Brachytherapy • ~75% single lumen single entry • ~25% multiplanemulticatheter Smith GL et al, SABCS 2011

8. Medicare Study Cohort: Exclusions • Metastatic disease at diagnosis • History of breast cancer • Non-continuous/ HMO insurance coverage • Radiation treatment type not known • Radiation using WBI plus brachytherapy Smith GL et al, SABCS 2011

9. Patient Characteristics Characteristic Median follow-up Mean age White race Axillary surgery Chemotherapy Axillary nodes involved Value 3.84 yrs 75 yrs 92 % 76 % 14 % 12 % Smith GL et al, SABCS 2011

10. Radiation Treatment Treatment Brachytherapy WBI Total % 6% 94% N 7,291 123,244 130,535 Smith GL et al, SABCS 2011

11. Subsequent Mastectomy Risk Brachytherapy 4% P < 0.001 WBI 2% Courtesy of Dr. Grace Smith

12. Increased Risk for Mastectomy Mastectomy Adjusted HR 2.22 1.00 P <0.001 95% CI 1.89 – 2.61 – Brachytherapy WBI Adjusted for: Age, race, comorbidities, treatment, year diagnosis, region, SES Courtesy of Dr. Grace Smith

13. Subgroups: Mastectomy Risk Subgroup HR 95% CI 2.83 – 7.76 1.73 – 2.45 P <0.001 <0.001 4.69 1.00 2.06 1.00 Axillary node + Brachytherapy WBI Axillary node ─ Brachytherapy WBI No modifying effect seen with: Age, race, comorbidity, chemotherapy, year, region Courtesy of Dr. Grace Smith

14. Overall Survival: No Difference Survival Brachytherapy WBI Adjusted HR 0.93 1.00 P 0.22 95% CI 0.83 – 1.05 – Adjusted for: Age, race, comorbid, treatment, year diagnosis, region, SES Not surprising, since there is no survival difference for whole breast RT vs. no RT in elderly Stage I patients Courtesy of Dr. Grace Smith

15. Postoperative Complications at 1yr: Increased Risks for Brachytherapy Infectious Non-infectious OR 1.75 1.99 P <0.001 <0.001 95% CI 1.60 – 1.87 1.86 – 2.13 Adjusted for: Age, race, comorbid, treatment, year diagnosis, region, SES Courtesy of Dr. Grace Smith

16. Brachytherapy: Excess Complications Over Time Courtesy of Dr. Grace Smith

17. Post-radiation Complications: 5 years Any Rib fracture Fat necrosis Breast pain RT pneumonitis Outcome Brachy (%) WBI (%) P 26 4.2 9 15 0.1 <0.001 0.03 <0.001 <0.001 <0.001 18 3.6 4 12 0.8 Courtesy of Dr. Grace Smith

18. Brachytherapy vs. WBI: Summary • Breast brachytherapy associated with increased risks of: • Subsequent mastectomy (failure of breast preservation) • Acute- and long-term toxicities • Mastectomy risk doubled, but small absolute difference in risk Courtesy of Dr. Grace Smith

19. Limitations • Older patients • Early generation of brachytherapy techniques • No single-entry multilumen devices • Subsequent mastectomy could be due to recurrence, toxicity, or contralateral cancer • Medicare claims data does not distinguish side or cause • Treatment and outcome data are claims-based • Pathology/ staging not available Courtesy of Dr. Grace Smith

20. Avoid Overestimating the Importance of These Limitations • Older patients: complications ?higher but failures lower • Early generation of brachytherapy techniques: multilumen devices can decrease complications, but not necessarily failures • Subsequent mastectomy could be due to recurrence, toxicity, or contralateral cancer: mastectomy risks in this study consistent with recurrence risks in prior studies • Treatment and outcome data are claims-based: inherentlimitations; still the largest cohort study to date on PBI • Pathology/staging not available: major issue. Possibility of inappropriate selection of PBI candidates

21. Partial breast irradiation randomized trial update: NSABP B-39/RTOG 0413 Julian TB et. al. (abstract OT2-06-02)

22. PBI versus WBI: B-39/04-13 2007: closed to low risk patients (age≥50 with DCIS or invasive ER+ node-) • 1° endpoint: Local control • 2° endpoints: DF, OS, • cosmesis, side effects 2011: single entry multilumen allowed (MammoSite, Contura, SAVI)

23. NSABP B-43/RTOG 0413 Single institution data has previously shown excess toxicities with 3D-conformal RT (3D-CRT), but this has not been demonstrated in the B-43 3D-CRT study population: Julian TB et al, SABCS 2011

24. NSABP B-43/RTOG 0413 • Largest phase III trial on APBI • Only phase III trial testing all 3 APBI techniques • Not stratified by APBI technique! • Accrual through 10/31/2011: 4023/4300 • Estimated completion date: March 2013 • Complete accrual critical; protocol given priority status by the Coalition of Cancer Cooperative groups Julian TB et al, SABCS 2011

25. Whole breast irradiation (WBI) vs. intraoperative PBI +/- WBI: update of the TARGIT-A trialVaidya JS et. al. (abstract P3-13-07)

26. WBRT vs. intra-op PBI +/-WBRT: TARGIT-A Vaidya JS at al, Lancet 2010

27. TARGIT-A: Patient Characteristics Low risk patient population: Age 55 or older: >80% ER positive: >80% Tumor ≤ 2cm: >80% Grade 1-2: ~80% LN negative ~80% Vaidya JS at al, Lancet 2010

28. TARGIT-A: 4-Year Results • Number of recurrences: Lancet 2010: 13/2322 SABCS 2011: 23/2322 • Kaplan-Meier 4-yr total local recurrence rate: Lancet 2010: 1.08% (95% CI 0.59-1.96) IO-PBI 1.20% WBI .95% (p=NS) SABCS 2011: 1.28%(95% CI 0.73-2.11) • TARGIT-B to open soon: • Intra-op boost vs. boost after external beam RT, in women ≤45 or at high risk of local recurrence Vaidya JS at al, SABCS 2011

29. TARGIT-A: Patient Characteristics Low risk patient population: Age 55 or older: >80% ER positive: >80% Tumor ≤ 2cm: >80% Grade 1-2: ~80% LN negative ~80% Rather than administer complex and expensive treatment, can we simply omit RT for these low risk patients? Vaidya JS at al, Lancet 2010

30. Molecular subtype and radiation response in patients with T1 N0 breast cancer: subset analysis of a randomized trialFyles A et. al. (abstract S2-2)

31. Age ≥50 Tumor ≤5cm Node negative BCS +/- ALND Tamoxifen x 5 years Tam + RT (40 Gy + 12.5 Gy boost) Omission of RT for Elderly Patients: Canadian Trial Median age 68 83% T1 Primary endpoints: IBTR, DM, OS Fyles, NEJM 2004

32. Omission of RT for Elderly Patients: Canadian Trial p<.001 No difference in DM or OS Fyles, NEJM 2004; ASTRO 2006

33. Omission of RT for Elderly Patients: Canadian Trial Planned subgroup analysis: tumor ≤2cm ER+ Unplanned subgroup analysis: age ≥60 tumor ≤1cm ER+ p<0.001 p<0.001 • Small number of women • Further failures expected with longer follow-up Fyles, NEJM 2004

34. Canadian Trial: 10-Year Results Fyles A, SABCS 2011

35. Canadian Trial: Tumor Subtype and Radiation Response • Molecular subtype determined using semi-quantitative analysis of ER HER2 PR EGFR Ki-67 CK 5/6 • Analysis performed on 172/769 women • Patients classified into: Luminal A Luminal HER2 Basal-like Luminal B HER2-enriched Triple negative Fyles A, SABCS 2011

36. Canadian Trial: Results By Molecular Subtype The Luminal A subgroup represents a substantial proportion of older patients, who can be safely spared the inconvenience and side effects of RT Fyles A, SABCS 2011

37. Boost treatment after whole breast RTfor patients with DCIS: results from the NSABP B-24 trial Julian TB et. al. (abstract P3-13-01)

38. Tamoxifen for DCIS: NSABP B-24 +Margins OK Extensive calcs OK Tumor bed boosting: • Boost status and other pertinent data known for 1392 patients • 613/1392 received a boost • 85% of boosted patients received a 10 Gy boost • Mean follow-up time 161 months Fisher B et al, Lancet 1999; Julian TB at al, SABCS 2011

39. NSABP B-24: Predictors of Boost Treatment • Patients were more likely to receive a boost if: Younger age (≤49) p=.04 Comedo necrosis p=.03 Positive margins p=.007 Julian TB at al, SABCS 2011

40. NSABP B-24: Multivariate Analysis of IBTR Boost treatment had no significant effect on IBTR: • Noboost effect for invasive ornoninvasive IBTR: Julian TB et al, SABCS 2011

41. Ongoing randomized trial: Boost treatment after whole breast RT for DCISAzria D et. al. (abstract OT2-06-01)

42. WBI +/-Boost for DCIS: BONBIS Trial (France) 1°endpoint: Ipsilateral breast events 2° endpoints: toxicity, cosmesis, QOL Azria D et al, SABCS 2011

43. Oncotype DX® for DCIS: a prospective validation from ECOG 5194Solin LJ et. al. (abstract S4-6)

44. Omission of RT for DCIS: ECOG 5194 Observational Study • Wide excision alone for “favorable” DCIS • Grade 1-2, size <2.5 cm • Grade 3, size <1 cm • Margins ≥3 mm • Negative postoperative mammogram • Tamoxifen allowed Hughes, JCO 2009

45. Grade 1-2 580 patients Median tumor size 6mm Median margin 5-10mm 31% declared intention to take tamoxifen 5-yr local failure rate 6.1% Grade 3 102 patients Median tumor size 7mm Median margin 5-10mm 30% declared intention to take tamoxifen 5-yr local failure rate 15.3% Omission of RT for DCIS: ECOG 5194 Outcomes *Grade assignment based on local pathology review* Hughes, JCO 2009

46. Development of the DCIS Score • Goal: develop a genomic-based score to predict local recurrence, regardless of tamoxifen use • Gene selection: a subset of Oncotype DX RS genes prognostic in tamoxifen treated and untreated patients Proliferation Group Ki67 STK15 Survivin CCNB1 (cyclin B1) MYBL2 Hormone Receptor Group PR Reference Group ACTB GAPDH RPLPO GUS TFRC GSTM1 • DCIS Score evaluated as a continuous variable and in 3 prespecified risk groups (low, intermediate, high) • Unlike DS RS, the DCIS Score does not use thresholding Solin LJ et al, SABCS 2011

47. DCIS Score and ECOG 5194: Study Population • Tumor tissue for DCIS Score testing available in 327/670 E5194 patients (49% of parent study) • Patients characteristcs in study group similar to that in parent study • Median f/u in this group: 8.8 years • Tumor grade assessed by central review • “Significant” discrepancies for local vs. central tumor grading Solin LJ et al, SABCS 2011

48. DCIS Score and ECOG 5194: Outcomes Risk-group stratified DCIS Score predicted for IBE independent of tamoxifen use Continuous DCIS Score (adjusted for tamoxifen use) also predicted IBE: HR 2.34 per 50 units; 95% CI 1.15, 4.59; p=0.02 Solin LJ et al, SABCS 2011

49. DCIS Score and ECOG 5194: Multivariable Models of IBE Risk Hazard Ratio 1.54 0.49 2.41 1.52 0.49 P value .01 .02 .02 .01 .02 Excluding the DCIS Score Tumor Size Postmenopausal Including the DCIS Score DCIS Score Tumor Size Postmenopausal Contrast to Oncotype DX RS for invasive cancer, which predicts recurrence independent of age and tumor size Solin LJ et al, SABCS 2011

50. 2nd annual San Antonio breast cancer symposium reviewjanuary 28, 2012 Sponsored By: