1. Radiation Breast Oncology Highlights of SABC 2006 Alison Bevan, MD PhD UCSF Radiation Oncology January, 2007

2. Topics I. Updates a. Evaluating the impact of adjuvant radiation in older women with ER+ ESBC on Tamoxifen (# 11) b. Who needs a boost? Defining radiation dose (#10) c. MammoSite TM (ASTRO #52) II. New a. DCIS: Who can avoid RT (#29) b. EBCTCG Meta-Analysis (ASTRO #4, SABC #40) ) IV. Conclusions I.Ongoing II.Conclusions

3. Radiation dose: who needs a boost to decrease LRR? Whole breast radiotherapy is delivered over 5 to 6 weeks. Boost is delivered over the last 5-8 days to the tumor bed Cost from patient’s point of view: time and toxicity Prior to EORTC trial, no guidelines

4. EORTC Boost Trial Bartelink, H., et al. NEJM, 2001 >5500 patients with stage I&II 50Gy (5 weeks) ± 16Gy boost (8 days) after complete excision Systemic therapy decreased LRR (HR.75) but disappeared in multivariate analysis P<.0001 BoostNo Boost 5y LRR4.3%7.3%

5. EORTC Boost Trial Bartelink, H., et al. NEJM, 2001 Benefit was age-related, particularly important for those younger than 50 years No difference in DM, OS BoostNo Boostp value LRR4%7%<.001 <40y10%19.5%.002 >60y2.5%4%.14

6. Randomized trial evaluating 10 Gy boost (Lyon Trial) Romestaing, P et al, JCO 1997 1024 women with tumors <3cm with negative margins 5 yearsBoostNo boost LRR3.6%4.5%

7. Impact of boost on LRR, cosmesis & survival 10 year results Bartelink H et al., EORTC 22881-10882 Abstract #10 No difference in OS (82%, p.93) Fibrosis increased with boost 4.4% v 1.6% p<.0001 Cumulative LRR 10% v 6% All statistically significant ageBoost No Boost Absolute benefit ≤4013.5%24%10.5% 41-509%12.5%4% 51-605%8%3% >604%7%3%

8. Impact of boost on LRR, cosmesis & survival 10 year results Bartelink H et al., EORTC 22881-10882 Abstract #10 Benefit in all ages Despite some poor boost techniques Is absolute benefit of 3% critical?

9. Impact of boost on LRR, cosmesis & survival 10 year results Bartelink, H et al., EORTC 22881-10882 Abstract #10 The boost is very important for young patients <35y and less important with increasing age Also incomplete excision arm consisting of 255pts randomized to 10Gy v 26Gy with increased local control (NS) & severe fibrosis New studies: microarrays to distinguish pathological features

10. Early Breast Cancer Trialists Collaborative Group (EBCTCG) Meta-analysis 1995 Post-operative radiation significantly reduced breast cancer deaths but increased non-breast cancer deaths resulting in no significant improvement survival. 2000 Significant reduction isolated local recurrence and breast cancer mortality with radiation but increase in non-breast cancer deaths with a non-significant benefit overall survival at 20 years.

11. Effects of radiotherapy and differences in the extent of surgery for early breast cancer on local recurrence and 15 year survival: An overview of the randomized trials Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Lancet 366: 2087-2106, 2005 ASTRO abstract #4, 2006 SABC abstract #40, 2006

12. EBCTCG: local therapies No. Trials No. women Total (by 1995) 78 42,080 CS +/- RT 10 7,311 Mastectomy +/- RT 36 16,177 Mastectomy vs. CS +/- RT 11 6,615 Nodal surgery vs. RT 9 4,550 Nodal surgery vs. none 8 2,502 RM vs. MRM 4 4,925

13. EBCTCG: endpoints for trial comparison 5 year isolated LRR (75% occurred within 5 years) 15 year breast cancer mortality 15 year all cause mortality

14. EBCTCG: breast cancer specific survival benefit at 15 years Trials with <10% absolute difference in 5 year isolated local-regional recurrence 15 year breast cancer mortality benefit 1% (M±RT N-, MRM v RM, M v CS+R) Trials with 10-20% absolute difference 15 year breast cancer mortality benefit 4.5% (CS±R n-, M ±R n+, axillary dissection v no axillary treatment) Trials with >20% absolute difference 15 year breast cancer mortality benefit 6% (CS ±R n+, M without axilllary dissection ±R n+)

15. EBCTCG: BCS trials Radiotherapy After BCS, 10 trials with 7311 women RTNo RT absolute benefit 5y LRR 7%26%19% 15y breast ca mortality 30.5%35.9%5.4% Overall mortality reduction 5.3%

16. LRR N0 16% N+ 30% EBCTCG: BCS & RT 5% 7% 15y absolute survival benefit (Mastectomy N+ 5%)

17. EBCTCG: local therapy comparisons For the women who received adjuvant systemic therapy: 5y isolated LRR No Systemic therapy 28% Systemic therapy 8% 15y reduction breast ca mortality 6% Better local treatment adds to the effects of systemic therapy on LR and breast cancer mortality

18. EBCTCG: local therapy comparisons 5 yr. Isolated Loc-reg Node - Node + Decrease breast cancer mortality 15 yr. Node - Node + Mastectomy +/- RT Mastectomy Mastectomy + RT 6% 23% 2% 6% +4% - 5% Mastectomy, CS+RT Mastectomy CS+RT 5% 8% 9% 5% +1% -2% CS +/- RT CS CS + RT 23% 41% 7% 11% -5% - 7%

19. EBCTCG: toxicity & OS Radiotherapy was associated with a significant increase in contralateral breast cancer at 15 years (7.5% vs. 9.3%) Radiotherapy was associated with a significant increase in non-breast cancer deaths at 15 years (14.6% vs. 15.9%) The excess mortality was primarily from heart disease and lung cancer

20. EBCTCG: local therapy comparisons Rule of 4 Proportional relationship between effects on local control and breast cancer mortality: “One breast cancer death (in the absence of any other causes of death) would be avoided for every 4 local recurrences prevented.” 4:1 local recurrence benefit/breast cancer survival benefit

21. EBCTCG: local therapy comparisons Rule of 4 For example: LRR without RT26% LRR with RT10% Absolute benefit = 16% at 5 years then survival benefit 4% at 15 years

22. Lumpectomy + Tamoxifen with & without XRT for Women ≥70 years with Early Stage Breast Cancer Hughes, KS et al. CALGB 9343, RTOG, ECOG Abstract #11 8.2 year follow-up (5yr NEJM, 2004) About 200pts in each group had no axillary exploration ≤2cm, cN0, ER+ TamRTTam ≥70 years Lumpectomy (631pts)

23. Lumpectomy + Tamoxifen with & without XRT for Women ≥70 years with Early Stage Breast Cancer Hughes, KS et al. CALGB 9343, NEJM, 2005 5 yearTamRTTamp value LRR1%4%p<0.0001 OS87%86%p=0.94 FFDM99%98%p=0.97 Mastectomy Free 99%98%p=0.15

24. Lumpectomy + Tamoxifen with & without XRT for Women ≥70 years with Early Stage Breast Cancer Hughes, KS et al. CALGB 9343, RTOG, ECOG Abstract #11 8.2 yearsTamRTTamp value LRR1% (4)7% (23)<.001 In-breast1% (4)6.3% (20)sig Axillary rec01.2%(4)sig Mastectomy rate1%3%NS Distant mets3% NS BSS2% NS Mortality27%26%NS

25. Lumpectomy + Tamoxifen with & without XRT for Women ≥70 years with Early Stage Breast Cancer Hughes, KS et al. CALGB 9343, RTOG, ECOG Abstract #11 Absolute LRR difference of 5-6% No statistical difference in mastectomy rate, distant metastases, BSS, OS Cosmesis inferior in TamRT arm No thromboembolic events Conclusion: reasonable option for some patients

26. Lumpectomy + Tamoxifen with & without XRT for Women ≥50 years with Early Stage Breast Cancer Fyles, AW et al, NEJM 2004 & ASTRO abstract #8 2006 (PMH) T1/T2N0 ER+ Median age 68y No association with age ER+ T1 had 9.9% versus 4.4% (≥60y: 7% v 3.7% p=.02) Tumors ≤1cm, 6.7% v 3% % at 8yTamRTTamp IBR4.112.2<.0001 Axillary Rec1.22.9.08 DFS8276.046 DM5.63.8.075 OS89.67

27. Comparison of Trials authoryearscharacteristicsLRR Hughes8≥70, T1 ER+ cN07% v 1% Fyles8≥60, T1 ER+ cN ±9.9% v 4.4% Veronesi10 Quad, ±N, ≤2.5cm >65≤70 56-65 (low numbers n=80, 25) 4.4% v 4% 12.1%v 2.4%

28. Considerations Age Hormone Receptor + Toxicity of Tamoxifen Co-morbidities Life expectancy Patient preference

29. MammoSite TM : multi-institutional 2 year experience with ESBC Cuttino, LW, et al ASTRO abstract #52 9 institutions, 2000-2004 483 patients with stage 0, I, II In-breast failure in 6 pts, 4 outside lumpectomy site Closed cavity placement reduced risk of infection from 9% to 4.8% Infection related to overall cosmesis being fair to poor Cosmesis good/excellent in 91%

30. Lumpectomy alone for low risk DCIS 5 year results of intergroup trial E5194 Hughes, L et al., ECOG, NCCTG Abstract #29 711 patients with DCIS enrolled from 1997-2002 (29 ineligible) Median age 60 years (range 28-88) Median f/u was 4.96 years Adjuvant Tamoxifen allowed in 2000 (ER status testing routine) All pathology reviewed at Vanderbilt University 89% acceptable for study after central review (excluded size <3mm)

31. Lumpectomy alone for low risk DCIS 5 year results of intergroup trial E5194 Hughes, L et al., ECOG, NCCTG Abstract #29 DCIS Group I Group II Lumpectomy (711 pts) Low/int grade <2.5cm High grade <1cm Observation 30% Tamoxifen Post-op mammogram clear for calcifications Margins>3mm

32. Lumpectomy alone for low risk DCIS 5 year results of intergroup trial E5194 Hughes, L et al., ECOG, NCCTG Abstract #29 Low-Int grade(580 pts) median tumor size 6mm 18% >1cm. median margin 5-10mm. 31% declared intention for TAM High grade (102 pts) median tumor size 7mm Median margin 5-10mm 30% declared intention to take TAM Ipsi breast events 13.7% 6.8% 50% DCIS and 50% Invasive Contralateral events 3.5% & 4.2%

33. Lumpectomy alone for low risk DCIS 5 year results of intergroup trial E5194 Hughes, L et al, ECOG, NCCTG Abstract #29 1.Observation is acceptable for rigorously evaluated and selected patients with low to intermediate grade DCIS of the breast 2.For high grade lesions (Grade 3), excision is inadequate 3.Early data, need longer f/u 4.Who got Tam, LRR with grade, age and margins status?

34. Prospective Study of Wide Excision Alone for DCIS of the Breast Dana Farber/Brigham and Woman’s CC 158 pts, median age 51 ≥1cm margins, Grade 1/2 (50/50), ≤2.5cm by mammo No Tamoxifen Rate of ipsi recurrence was 2.4% per year 5 year rate of 12% Closed early--met stopping rules 84% re-excision, 6% multiple re-excisions Wong, J et al. JCO, 2005 ?younger, larger tumors, no Tamoxifen?

35. Conclusions Boost: benefit in all age groups Tamoxifen without radiation after local excision for some ≥ 70 years women with ER+ ESBC may be acceptable EBCTCG: local control benefits breast cancer survival at 15 years Low-risk DCIS: no adjuvant radiation may be needed for small tumors with wide margins MammoSite TM trials are immature; closed technique superior in reducing infection

36. DCIS Collaborative Group CS+RT in 1003 pts LRR5y10y15y Solin5%10%19%