2017 Topics. Biology of Breast Cancer. Omission of RT in older women with low-risk features

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1 2017 Topics Biology of Breast Cancer Early-stage HER2+ breast cancer-can we avoid RT? Prediction tools for locoregional recurrence Omission of RT in older women with low-risk features

2 Local-Regional Recurrence in Women with N0/N1mi, HER2-Positive Breast Cancer: The APT Trial Jennifer R. Bellon, M.D., FASTRO Dana-Farber Cancer Institute Brigham and Women s Hospital Harvard Medical School

3 Biologic Subtype Tumor biology is at least as important in predicting behavior and outcomes as classical clinicopathologic features LRR varies by biologic subtype in patients receiving RT and in those treated with surgery alone, and is particularly low in patients with ER+ disease in an era of effective long-term endocrine therapies

4 Subtype is Prognostic for Local Recurrence No herceptin HER2 (No Herceptin) Triple - Lum A Lum B Lum-HER2 Arvold N et al. JCO 2011; 29(29)

5 The APT Trial Adjuvant Paclitaxel (T) and Trastuzumab (H) x 12 wks Prospective single arm study Eligibility - HER2 positive primary tumor (3+ IHC and/or FISH ratio >2) - Tumors smaller than 3.0 cm - N0 or N1mi (less than or equal to 2 mm) Systemic therapy - Weekly T (80 mg/m 2 ) - Weekly H (4 mg/kg week 1, then 2 mg/kg) - Additional H to complete one year (weekly or q3 wk, 6 mg/kg) RT doses and fields not specified Tolaney SM et al, NEJM (2):134-41

6 Patient Characteristics Age < >70 Size of Primary Tumor T1a T1b T1c T2 Grade I II III ER and/or PR Positive Negative Nodes (mi+) Positive Negative N %

7 Radiation Details Mastectomy (n= 162) - RT records available for 160 (99%) - None received PMRT Breast conservation (n=244) - RT record available for 217 (89%) 9 (4%) underwent APBI 208 (96%) received whole breast RT; of these, 202 (97%) had a boost No patient had a separate nodal field

8 DFS 7-Year Disease-Free Survival 1.00 All patients 93.3% (95% CI, %) BCS 92.1% (95% CI, %) Mastectomy 95.2% (95% CI, %) Number at risk BCS Mastectomy

9 LRR-free survival 7-Year Local/Regional Recurrence- Free Survival 1.00 BCS 99.0% (95% CI, %) Mastectomy 98.0% (95% CI, %) Number at risk BCS Mastectomy

10 LRR as a First Site of Recurrence Mastectomy patients (n=162) - Three recurred in the axilla (1.9%) Two patients had 0/3 SN One had 0/1 SN One was hormone receptor negative; 2 hormone receptor positive Breast conservation patients (n=244) - Two recurred in the breast (0.8%) 46.0 Gy in 23 fractions WB followed by 14 Gy in 7 fractions CD Gy in 16 fractions WB followed by 9 Gy in 3 fractions CD Both hormone receptor positive

11 Conclusions In patients with early-stage disease receiving HER2-directed therapy, local recurrence rates are extremely low ( % at 7 years)

12 Hypothetical Benefit of Local Tumor Control on Survival with Increasing Effectiveness of Systemic Therapy. Punglia RS et al. N Engl J Med 2007;356:

13 Hypothetical Benefit of Local Tumor Control on Survival with Increasing Effectiveness of Systemic Therapy. NSABP B-04 Punglia RS et al. N Engl J Med 2007;356:

14 Hypothetical Benefit of Local Tumor Control on Survival with Increasing Effectiveness of Systemic Therapy. Danish trials Punglia RS et al. N Engl J Med 2007;356:

15 Hypothetical Benefit of Local Tumor Control on Survival with Increasing Effectiveness of Systemic Therapy Are we here for HER2+ patients? Punglia RS et al. N Engl J Med 2007;356:

16 Future Directions Ongoing efforts should be directed at selectively deescalating local therapy in HER2+ patients receiving effective anti-her2 treatment Potential avenues for study: Omitting the routine use of a lumpectomy site boost Omitting radiation in patients with a complete response to preoperative systemic therapy Omitting nodal radiation and/or PMRT in patients with limited axillary involvement

17 Can ER+ Patients Avoid RT After BCS? The holy grail: finding a low-risk population of patients in whom the risk of recurrence in the absence of RT is sufficiently small that omission of RT might reasonably be considered after BCS Risks of IBTR falling due to improvements in screening, surgical practice, and systemic rx Studies to date, including all ER+ patients based upon clinicopathologic characteristics alone, have largely proven unsuccessful

18 NSABP B-21 Can tamoxifen might be utilized in lieu of RT in selected patients? 1009 women w 1 cm IBC after lumpectomy randomized to tamoxifen, RT, or both ER testing not required 20% of patients <50 Negative margins defined as no tumor on ink 8-year IBTR 16.5% with tam alone 9.3% with RT 2.8% with both Conclusion: adjuvant RT necessary even in patients with small tumors in the era of

19 Canadian Trial Patients 50+ with T1-2 node-negative breast ca randomized to observation vs RT after BCS and tamoxifen (Fyles et al. NEJM 2004) IBTR 8% vs 1% at 5 years At 8 years, 18% vs 4% Planned subgroup analysis of 611 women with T1, receptor-positive tumors: IBTR 6% vs 0.4% at 5 years and 15% vs 4% at 8 years

20 CALGB 9343 Patients 636 women, age 70+ Clinical stage I, ER+ Randomization Tamoxifen +/- RT 10-yr LRR 10% vs 2% (favoring +RT) no significant difference in DMs, breast cancerspecific mortality, or allcause mortality Impact on practice??

21 The 21-Gene Assay Recurrence Score as a Predictor of Local-Regional Relapse in Early Stage Breast Cancer M. Chadha, Z. Ghiassi-Nejad, S. Cate, A. Gillego, J. Wallach, S. K. Boolbol Mount Sinai Downtown Icahn School of Medicine at Mount Sinai New York

22 Background The RS is a validated prognostic tool that quantifies risk for DM in hormone receptor positive, Her2 negative breast cancer It also predicts the benefit from chemotherapy and is used to guide systemic therapy The 21-genes used for determining Recurrence Score (RS) Distant Relapse-free Survival Paik S, et al: N Engl J Med, 2005

23 21-Gene RS and Locoregional Recurrence There are limited data on the prognostic value of RS for localregional relapse Mamounas et al reported a significant association between RS and local-regional relapse in node negative, hormone receptor positive breast ca

24 Objectives Study the incidence of local-regional and distant relapse in hormone receptor positive, node negative breast cancer Examine the relationship between RS in addition to clinical-pathologic factors and risk of relapse Perform a subset analysis on patients treated with lump + RT

25 Methods We retrospectively identified 1355 breast cancer patients for whom the 21-gene assay RS was obtained as part of routine care Unilateral, node negative breast cancer with a minimum follow up of 2-years

26 Materials and Methods Patient characteristics (n= 792) Age: median (range) <50 years > 50 years T-size: < 2.0cm > 2.0cm Treatment: Mastectomy Lump +RT Syst. therapy prescribed: Hormonal therapy Chemotherapy 56 years (25-84 years) 30% 70% 81.4% 18.6% 26.5% 73.4% 96.9% 33.2%

27 Materials and Methods Patient characteristics (n= 792) 21-gene RS: Low <18 Intermediate High > % 37.4% 8.8% Histologic grade: Lymph Inv: Path margins: G1 G2 G3 Present Absent Negative Close/positive 26.0% 52.7% 15.8% 14.3% 85.8% 90% 9.3%

28 Results: Five-year Kaplan Meier Survival 99.1 % 93.6% Median follow up 55 months (range months)

29 Multivariate regression analysis for distant metastases Risk Factors Hazard Ratio (95% CI) p-value Age 1.06 (0.43, 2.58) T-size 6.60 (2.82, 15.44) <0.001 Grade 0.95 (0.84, 1.09) Lymph. Inv (0.65, 4.03) gene RS (1.65, 12.10) 0.003

30 Multivariate regression analysis for local-regional recurrence Risk Factors Hazard Ratio (95% CI) p-value Age 0.82 (0.32, 2.10) T-size 2.28 (0.87, 6.02) Grade 1.0 (0.98, 1.02) Lymph. Inv (1.09, 7.42) gene RS (1.08,7.36) Treatment Type 1.05 (0.39, 2.86)

31 Recurrence score and local-regional relapse Node negative breast cancer Clinical variable Mamounas et al n=895 Chadha et al n=792 Age (> 50 vs. < 50) Lymph. Inv Gene assay RS Mast. vs. Lump. + XRT

32 Recurrence score and risk of local-regional relapse (LRR) Lumpectomy + RT Mamounos et al, 2010 (NSABP-B14, B20) Number of patients Node status Relationship of RS and risk of LRR 390 Node negative <50 years > 50 years Chadha et al, Node negative Solin et al, 2012* 388 Node positive 0.21 Mamounos et al, 2017 (NSABP-B28) 461 Node positive 1-3 pos. nodes 0.13 > 4 pos. nodes 0.04 * Evaluation of the 21-gene recurrence score as a continuous variable showed a statistically significant hazard ratio for local regional recurrence (hazard ratio 2.66; P = 0.03)

33 Conclusions The 21-gene RS is significantly associated with risk for distant relapse In hormone positive, node negative study population, RS is significantly associated with risk for local-regional relapse However, in the patient subset treated with lump + RT, RS was not a significant predictor for local-regional relapse

34 Endocrine Therapy Alone After BCS for Selected Biologically Low-Risk Tumors? NOT THE STANDARD OF CARE BUT AN AREA OF ONGOING INVESTIGATION LUMINA Prospective multicenter cohort study in Canada Age 60+ Unifocal Stage I (pn0), lumpectomy, negative margins (2 mm), no lobular, no EIC, no LVI, no Grade 3 ER+/PR+/Her2- Luminal A tumors (by IHC; centralized Ki67 not >13%) IDEA Prospective multicenter cohort study in US (Michigan, MSKCC, Hopkins, Harvard/MGH, Harvard/BIDMC, Penn, Stanford, Yale, Loyola, MCW, ECU, UTSW, CINJ/Rutgers) Age Unifocal Stage I (pn0), lumpectomy, negative margins (2 mm) ER+/PR+/Her2- Low Oncotype-DX RS ( 18) PRECISION Prospective multicenter cohort study in Boston (DFCI/BWH) Age Criteria

35 Cumulative Incidence Rate What About After Mastectomy Patients with Positive Lymph Nodes? 1-3 Positive Nodes (N=386) >4 Positive Nodes (N=218) RS Low RS Intermediate RS High N LRR Events RS Low RS Intermediate RS High N LRR Events P-value = 0.64 P-value = % 6.0% 4.1% 2.4% 9.6% 5.5% Time in Years Time in Years Mamounas et al; JNCI 2017

36 MA node positive OR High risk node negative >5 cm or >2 cm and <10 nodes removed And grade 3 or LVI positive or ER negative Chemotherapy and/or endocrine therapy required Breast conservation whole breast radiation vs. whole breast + regional nodal RT Whelan TJ et al, NEJM 2015; 373:

37 Ten-year Results (n=1832) 10-Yr No Nodal RT Nodal RT HR p- value LRR* 6.8% 4.3% DFS 77.0% 82.0% OS 81.8% 82.8% Whelan TJ et al, NEJM 2015; 373: *isolated

38 Biologically Guided PMRT? ANOTHER AREA OF INVESTIGATION A pre-planned subgroup analysis of MA.20 demonstrated that regional RT was much less effective for ER+ compared to ER-

39 MA.20 DFS* ER+ve Luminal A-like ER+ve or PR+ve Luminal B-like HR=1.09; 95% CI HR=0.66; 95% CI 0.; Time (years) # At Risk(WBI) # At Risk(WBI+RNI) ER-ve, and PR-ve Time (years) # At Risk(WBI) # At Risk(WBI+RNI) HR=0.59; 95% CI *p for interaction = 0.05

40 Patient Views and Correlates of Radiotherapy Omission: A Population-Based Survey of Older Women with Favorable Prognosis Breast Cancer Dean Shumway, Kent Griffith, Sarah Hawley, Kevin Ward, Ann Hamilton, Steven Katz, Monica Morrow, and Reshma Jagsi September 24, 2017 Funded by NCI P01CA163233

41 CALGB 9343: Freedom from Ipsilateral Breast Tumor Recurrence at 10 Years 98% 91% Similar results from PRIME II, with 4% IBTR rate 5 years after radiotherapy omission Figure courtesy of Dr. Kevin Hughes

42 Objective To evaluate patient views and correlates of the decision to omit radiotherapy in a population-based survey study of older women and their surgeons

43 Methods The icancare study identified women from the Georgia and Los Angeles County SEER regions with early stage breast cancer 5,080 surveys were completed median 7 months after diagnosis; response rate 70% Survey responses linked to SEER data

44 Methods Analytic sample limited to 999 women age 65 with stage I-II unilateral invasive breast cancer treated with breast conserving surgery Separate survey completed by 240 surgeons who were linked to patients; response rate 77%

45 Results 14% of women age 65 omitted radiotherapy Among women who omitted radiotherapy, the most common reasons were: A physician told the patient that RT was not needed (54%) The decision was left to the patient and she chose not to receive RT (41%) Cost, burden on family, absence of discussion with doctor about RT were uncommon reasons for omitting RT (<5%)

46 Patient Perceptions on the 10-year Risk of Local Recurrence 20% 19% 18% 15% 10% 10% 5% 2% 0% RT Omission RT Receipt CALGB 9343 Patient perception

47 Correlates of Radiotherapy Omission Adjusted for race, income, education, insurance, marital status, BMI, and SEER site

48 Correlates of Radiotherapy Omission Adjusted for race, income, education, insurance, marital status, BMI, and SEER site

49 Correlates of Radiotherapy Omission Although there appears to be a trend for a surgeon level effect, ultimately this was not statistically significant

50 Conclusions To some extent, RT omission appears appropriately individualized based on age, ER status, and grade Higher RT omission in non-english speakers and lack of association with comorbidity suggest opportunities to improve individualized decisions Older women with a favorable prognosis (and many of their physicians) significantly overestimate their risk of local and distant recurrence

51 What We Can Offer Today Node-negative disease: Omission of RT altogether (appropriate in patients 70+; investigational in select others) Partial breast irradiation (lower absolute risks of recurrence) Hypofractionation (ER+ patients are particularly well represented in mature RCTs) Omission of boost (small absolute expected benefit unless young/high grade/close margins) Node-positive disease: Omission of ALND (well represented on Z011) Omission of PMRT or of nodal RT after BCS (MA20 OS advantage was in triple negatives)