CALGB 9343 Comparison of Lumpectomy Plus Tamoxifen With and Without Irradiation in Women 70 or Older with Clinical Stage I, ER+ Breast Carcinoma Kevin S. Hughes, Lauren A. Schnaper, Constance Cirrincione, Donald Berry, Beryl McCormick, Hyman B. Muss, Clifford Hudis, Eric Winer, Barbara L. Smith Cancer and Leukemia Group B Radiation Therapy Oncology Group Eastern Cooperative Oncology Group 1

CALGB 9343 R A N D O M I Z E Radiation Tamoxifen Tamoxifen ELIGIBILITY Age ³ 70 Clinically Node Negative Lumpectomy, Negative Margin Tumor size £ 2 cm ER Positive or Indeterminate R A N D O M I Z E Radiation Tamoxifen Tamoxifen 2

Objections to this study Patients randomized to receive no radiation would be inappropriately under-treated Patients randomized to receive radiation therapy would be inappropriately over-treated

CALGB 9343 Opened July 15, 1994 Closed February 26, 1999 647 patients Eligible 631 Ineligible 5 Canceled/Never treated 11 Median follow-up 12 years

Patient characteristics RT+Tam Tam Total treated 317 319 Age >75 176 (56%) 172 (54%) ER Positive 308 (97%) 310 (97%) Size < 2cm 295 (93%) 296 (93%) No Ax dissection 200 (63%) 203 (64%)

IBTR (Ipsilateral Breast Tumor Recurrence) 21 women TamRT Tam (N=317) (N=319) Events 6 (2%) 27 (9%) p=0.0001

Ultimate mastectomy TamRT Tam Events (N=317) (N=319) 4 (2%) 10 (4%) p=0.1779

IBTR 6 4 RT Mastectomy 10 IBTR 27 17 Lumpectomy No RT

Axillary recurrence TamRT Tam 317 319 No ax dissection 200 203 Ax Recurrence 6 (3%)

Free of Second Primary Cancer TamRT Tam (N=317) (N=319) Events 36 (12%) 33 (9%) p=0.7268

Overall Survival TamRT Tam Events (N=317) (N=319) 157 (33%) 166 (33%) P=0.8045

Free from distant metastasis TamRT Tam (N=317) (N=319) Events 21(5%) 16 (5%) P=0.461

Breast cancer specific survival TamRT Tam (N=317) (N=319) Events 12 (3%) 8 (2%) P=0.4115

Ultimate Outcome

Benefits of RT are small 21 women TamRT Tam N=317 N=319 N (10 years) Breast Recurrence 6 (2%) 27 (9%) p=0.0001 Ultimate Mastectomy 4 (2%) 10 (4%) NS Second primary cancer 36 (12%) 33 (9%) Distant metastasis 21(5%) 16 (5%) Death 157 (33%) 166 (33%) Death Other Causes 145 148 Death from breast cancer 12 8 N (% at 10 yeas) N (% at 10 years)

Ultimate breast preservation NS Second primary cancer NS CONCLUSION: In older women, the benefits of radiation after lumpectomy are small 21 women Breast recurrence ~7% Radiate 319 women to avoid 21 in breast recurrences Ultimate breast preservation NS Second primary cancer NS Distant metastases NS Death breast cancer NS Death from any cause NS

Ultimate breast preservation NS Second primary cancer NS CONCLUSION: In older women, the benefits of radiation after lumpectomy are small 21 women Breast recurrence ~7% Radiate 319 women to avoid 21 in breast recurrences Ultimate breast preservation NS Second primary cancer NS Distant metastases NS Death breast cancer NS Death from any cause NS Study is mature: 12 years Median, Half of patients dead With modern margins and AI’s, RT will likely have even less benefit

Ultimate breast preservation NS Second primary cancer NS CONCLUSION: In older women, the benefits of radiation after lumpectomy are small 21 women Breast recurrence ~7% Radiate 319 women to avoid 21 in breast recurrences Ultimate breast preservation NS Second primary cancer NS Distant metastases NS Death breast cancer NS Death from any cause NS Omitting Radiation in women 70 and above with Clinical Stage I breast cancer is a reasonable alternative for our patients

CALGB 9343 enrolled 647 patients CALGB 9343 enrolled 647 patients. Eleven patients never began protocol therapy; findings are based upon the 636 patients who began protocol treatment. As of May 2010, the median follow-up for treated patients was 12 years with a maximum of 16 years. Three hundred nine (309) patients are alive and in active follow-up. Two hundred thirty-nine (239, 77%) of them have survived at least 10 years from enrollment. Only four patients (<1%) have been lost to follow-up, and only 10 patients (1.5%) withdrew consent to be followed. Table 1. Patient enrollment Tam + RTTamTotalTotal enrolled323 (100%)324 (100%)647 (100%)Never began Rx6 (2%)5 (2%)11 (2%)Treated317 (98%)319 (98%)636 (98%) Data as of May 2010 Median follow-up = 12 years (range = 1, 16) Table 2. First event The table below describes the first recurrence: local, distant or local and distant synchronously. Because the entries are for first recurrence, a patient may only be counted once. StatusArmTotalTam + RTTamTreated317 (100%)319 (100%)636 (100%)Total recurrences234164Type of recurrencea. Local only42832 In breast only ( 4) (22) (26) Axillary only ( 0) ( 5) ( 5) In-breast + axillary ( 0) ( 1) ( 1)b. Distant only171128c. Local + distant *224 * All local recurrences were IBTR only. Table 3. 10-year incidence of each study endpoint by treatment arm This table considers the occurrence of each event at any time in follow-up. It is therefore unlike Table 2, which is restricted to site of first recurrence only. A patient may have an event for each of the five endpoints. ArmEndpointFree from local recurrenceWithout subsequentmastectomyFree from distant metsOSBC-specific survivalTam + RT98%(96-99%)98%(96-99%)95%(92-97%)67% (61-72%)97%(94-99%)Tam90%(85-93%)96%(93-98%)95%(91-97%)67%(61-72%)98%(95-99%) Table 4. Comparison by treatment arm of entire distribution of each endpoint EndpointTime to local recurrenceTime to subsequent mastectomyTime to distant metsOSBC-specific survivalP-value from logrank test0.00010.180.460.800.41 Table 5. Second primaries SiteArmTotalTam+RTTamBreast Invasive9918 DCIS213 Lymph nodes101Blood AML112 CLL011 MDS011Lymphoma Lymphoma325 NHL112GI Abdomen011 Bowel101 Colon448 Epiglottis101 Peritoneum011 Rectum101 GI, NOS101GU Bladder101 Endometrium314Hepatic Liver022 Pancreas011 Spleen101Lung4711Melanoma202 Two patients had two new primaries.

Site Arm Total Tam+RT Tam Breast Invasive 9 18 DCIS 2 1 3 Lymph nodes Blood AML CLL MDS Lymphoma 5 NHL GI Abdomen Bowel Colon 4 8 Epiglottis Peritoneum Rectum GI, NOS GU Bladder Endometrium Hepatic Liver Pancreas Spleen Lung 7 11 Melanoma

Time to local recurrence Time to subsequent mastectomy Endpoint Time to local recurrence Time to subsequent mastectomy Time to distant mets OS BC-specific survival P-value from logrank test 0.0001 0.18 0.46 0.80 0.41

Free from local recurrence Arm Endpoint Free from local recurrence Without subsequent mastectomy Free from distant mets OS BC-specific survival Tam + RT 98% (96-99%) 95% (92-97%) 67% (61-72%) 97% (94-99%) Tam 90% (85-93%) 96% (93-98%) (91-97%) (95-99%)

Status Arm Total Tam + RT Tam Treated 317 (100%) 319 (100%) 636 (100%) Total recurrences 23 41 64 Type of recurrence a. Local only 4 28 32 In breast only ( 4) (22) (26) Axillary only ( 0) ( 5) In-breast + axillary ( 1) b. Distant only 17 11 c. Local + distant * 2

Tam + RT Tam Total Total enrolled 323 (100%) 324 (100%) 647 (100%) Never began Rx 6 (2%) 5 (2%) 11 (2%) Treated 317 (98%) 319 (98%) 636 (98%)

Can we? Should we? Patient factors are dependent on physiologic age Tumor factors are dependent on chronologic age

Concerns regarding this study Patients randomized to receive no radiation would be inappropriately under-treated

Concerns regarding this study Patients randomized to receive no radiation would be inappropriately under-treated Patients randomized to receive radiation therapy would be inappropriately over-treated

2007: Median 8.2 Yr

Axillary recurrence

Time to IBTR TamRT Tam Free from In-Breast Recurrence (N=317) (N=319) 20 women TamRT Tam (N=317) (N=319) Free from In-Breast Recurrence 6 (98%) 26 (92%) p=0.0001

Concerns regarding this study Patients randomized to receive no radiation would be inappropriately under-treated Patients randomized to receive radiation therapy would be inappropriately over-treated

Second Primary Cancer TamRT Tam TOTAL 36 (12%) 33 (9%) Breast 12 10 Leukemia 1 2 MDS Lymphoma 4 3 Colorectal 6 5 Epiglottis Peritoneum GI,NOS Liver Pancreas Spleen Bladder Endometrium Lung 7 Melanoma