The trend toward lesser treatment has already been employed in the surgical and medical management of breast cancer. In medical oncology, it was determined early that patients who are negative derive little benefit from anti-estrogen therapy or oophorectomy.1,2 More recently, genomic testing has allowed many patients with low-risk tumors to forego chemotherapy.3 In surgery, it has been clearly demonstrated that many women can undergo lumpectomy (with radiation) instead of mastectomy,4 and sentinel node biopsy instead of axillary dissection.5,6 In those requiring mastectomy, many can now have their nipple preserved.7 While radiation oncology has examined decreasing breast radiation with hypofractionation techniques8,9 and partial breast irradiation,10 there remains resistance to omitting radiation entirely, even in selected cases.
The acceptance of breast conservation in the 1980s is germane to the radiation discussion. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 was designed to study whether breast conservation was equivalent to mastectomy.4,11 Based on the 1985 analysis, lumpectomy with radiation was deemed an acceptable alternative to mastectomy despite the significant rate of ipsilateral breast tumor recurrence (IBTR) after conservation, because survival was no different than with mastectomy.12 In addition, this study introduced the idea of an acceptable IBTR rate. While survival was the same with or without radiation, the IBTR rate with radiation (7.7% at 5 years) was considered acceptable. The IBTR rate without radiation (27.9% at 5 years) was deemed too high. Thus, the validation of lumpectomy was based on the tolerance of a moderate amount of IBTR below a given threshold. The Eusoma Guidelines13 suggest that a 1% per year rate of IBTR is acceptable, which translates to 5% at 5 years and 10% at 10 years. Patients and physicians seem to find this threshold acceptable as evidenced by the acceptance of IBTR rates similar to this for women with triple-negative breast cancer,14 young women,15 those with high-grade DCIS,16 and those undergoing preoperative chemotherapy.17 While IBTR rates have continued to improve for many of these subgroups, conservation was still chosen by most physicians and patients even when the reported rates mirrored these thresholds.
Soon after the initial publication of NSABP B-06, the search began for subgroups that might not require radiation after breast-conserving surgery. In the pre-genomic era, characteristics chosen were combinations of older age, smaller cancers, and estrogen-receptor positive (ER+) cancers. NSABP B-21 evaluated women with ER+ tumors 1 cm or less at any age1; Fyles et al, assessed women with ER+ tumors up to 4 cm but over age 50,18 and CALGB 9343 (Cancer and Leukemia Group B, working with ECOG and RTOG) studied women aged 70 and above with ER+, clinical stage 1 breast cancers.19 All of these studies randomized patients to radiation versus no radiation, and most required tamoxifen use (though NSABP B-21 also had a ‘no tamoxifen’ arm). In each study, survival was not affected, and radiation therapy decreased the rate of IBTR, although this benefit was least in older women with smaller cancers. Other trials, such as PRIME 2 (Postoperative Radiotherapy in Minimum-Risk Elderly), have subsequently been published with similar results.20 It is important to note that overall survival was included in the pre-specified analyses of these studies, although information regarding the statistical power to detect differences was not provided for most of them, as the analyses focused on the primary endpoints related to recurrence.
CALGB 934319 accrued 631 eligible patients between July 15, 1994 to February 26, 1999. The median follow-up at the most recent publication was 12 years. Patient and tumor characteristics were evenly distributed between the two groups (Table 1). Locoregional recurrence was decreased by the use of radiation, with a 10-year rate of 10% in the tamoxifen alone group and 2% in the tamoxifen plus radiation group. Thus, there was a net 8% benefit from radiation in terms of locoregional recurrence. When axillary recurrences were excluded and only IBTR recurrences considered, the net benefit decreased to 7%.19
However, no additional benefits were identified. Radiation had no impact on survival, distant disease-free survival, or the ultimate rate of breast preservation (as many women who who had a recurrence in the breast after tamoxifen alone were still able to salvage their breast with repeat lumpectomy and subsequent radiation at the time of recurrence). Of note, this study was not powered to prove noninferiority with regard to survival.
These results were compelling and changed clinical practice guidelines. The current National Comprehensive Cancer Network (NCCN) guidelines state that women aged 70 and above with clinical stage 1 ER+ breast cancers may be treated with or without radiation.21 This change propagated into most quality measures (eg, Commission on Cancer, American Society of Clinical Oncology Quality Oncology Practice Initiative, and National Accreditation Program for Breast Cancer), each of whom changed the quality measure requiring radiation after lumpectomy for all patients to now apply only to women less than 70 years old. Unfortunately, this approach has been slow to disseminate into clinical care.22,23
Some have criticized the CALGB 9343 study, suggesting that while the study is true for many patients, it may not apply to those who are healthy.24,25 These critics may have overlooked the fact that most women in this study lived longer than would have been predicted for a group of women of comparable age, with more than 50% still alive at 12 years median follow-up.19 This study accumulated healthier women, and with a longer life expectancy, than an average group of women that age. Thus, poor health does not appear to explain these results, and these data apply to healthy older women.
Some suggest that while this study may be true for many patients, it may not apply to women with high-grade cancers, high-risk genomic scores, HER2 positive, and possibly other subgroups.24-26 However, there are no data to support these assertions, and yet many older women receive radiation due to these biases. Critics also contend that the 4% IBTR at 5 years and 9% IBTR at 10 years in CALGB 9343 are not acceptable.25,26 This criticism is interesting, as many breast cancer clinicians accept a similar rate of IBTR in patients receiving intraoperative or partial-breast irradiation (Table 2). The rates of IBTR in high-risk women getting whole breast radiation, in low-risk women not getting radiation, or in low-risk women getting partial breast radiation are acceptable, because we are moving away from the conflation of IBTR, which is accepted and expected in some cases after conservation, with distant recurrence, which is deadly. The acceptance of a finite level of IBTR made breast conservation possible, and a similar recognition is now circulating into the radiation field with the acceptance of conservation without radiation, or with less radiation, in select cases.
The outcome of CALGB 9343 was likely a result of the fact that older women tend to have less aggressive cancers that are more responsive to endocrine therapy.27-29 The results likely had less to do with age and more to do with the tumor itself. This has been strongly suggested by others who studied IBTR in younger individuals. For example, in a study of 151 women aged 60 and above with tumors <2 cm, grade 1 or 2, and luminal A subtype, the 10-year rate of IBTR was 1.3% with tamoxifen versus 5% with tamoxifen plus radiation therapy.30
The PRECISION Trial (Profiling Early Breast Cancer for Radiotherapy Omission) builds on this work,31 using genomic profiling to limit the use of radiation in a subgroup of women that would likely derive little benefit. In this single-arm study, patients who are ER+, PR+, HER2 negative, grade 1 or 2, and low risk by the Prosigna genomic assay, will be eligible for endocrine therapy without radiation. This study will show a finite rate of IBTR, and the investigators hypothesize that this rate will be acceptable (defined as acceptable if the upper limit of the 95% confidence interval for 5-year locoregional recurrence is below 5%).
We are now moving into an era where the cost of medicine must be contained, and the actual benefit of each therapy must be weighed carefully against cost. Radiation for women aged 70 and above with clinical stage 1, ER+ cancers is expensive and has minimal benefit. These women have much greater risk to their lives and well-being from other causes, with 94% of women who died in CALGB 9343 dying of something other than breast cancer.19 It is time to consider whether healthcare dollars are better spent on other more deadly aspects of their health rather than on radiation.
This will have implications for the financial status of radiation departments. Konski et al recently reported that the change to hypofractionation in breast cancer radiation will cause a per-case marginal reduction in reimbursement of $4,297.32 A similar analysis needs to be done for omitting radiation in older women, where the loss of revenue will be many times that amount, and the financial impact on radiation oncology departments will be profound. Fortunately, this may become more palatable as we move away from fee-for-service models and move towards accountable care and value-based medicine.
In summary, most women aged 70 and above with clinical stage 1, ER+ cancers do not need radiation therapy after lumpectomy. Furthermore, studies regarding the use of genomic signatures in younger women with low-risk tumors might ultimately demonstrate an additional subgroup that may avoid radiation therapy. Radiation oncologists are on the verge of joining breast surgeons and medical oncologists in decreasing the cost and morbidity of breast cancer treatment without negatively impacting survival or quality of life.
Affiliations: Jennifer K. Plichta, MD, and Kevin S. Hughes, MD, are from the Department of Surgery, Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA.
Address correspondence to: Kevin S. Hughes, MD, Massachusetts General Hospital, 55 Fruit Street, Yawkey 7, Boston, MA 02114. Telephone: (617)724-0048, Fax: (617)724-3895,
Disclosures: Kevin S. Hughes receives Honoraria from Myriad Genetics, Veritas Genetics, and is a founder of and has a financial interest in Hughes Risk Apps, LLC. Dr. Hughes’ interests were reviewed and are managed by Massachusetts General Hospital and Partners Health Care in accordance with their conflict of interest policies.
- Fisher B, Bryant J, Dignam JJ, et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol. 2002;20(20):4141-4149.
- Nomura Y, Tashiro H, Hisamatsu K, Shinozuka K. A randomized trial of adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy for operable breast cancer stratified by estrogen receptors. Cancer. 1988;61(11):2168-2175.
- Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015;373(21):2005-2014.
- Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347(16):1233-1241.
- Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA. 2011;305(6):569-575.
- Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: Overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol. 2010;11(10):927-933.
- Coopey SB, Tang R, Lei L, et al. Increasing eligibility for nipple-sparing mastectomy. Ann Surg Oncol. 2013;20(10):3218-3222.
- Haviland JS, Owen JR, Dewar JA, et al. The UK standardisation of breast radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14(11):1086-1094.
- Ortholan C, Hannoun-Levi JM, Ferrero JM, Largillier R, Courdi A. Long-term results of adjuvant hypofractionated radiotherapy for breast cancer in elderly patients. Int J Radiat Oncol Biol Phys. 2005;61(1):154-162.
- Smith GL, Xu Y, Buchholz TA, Giordano SH, Smith BD. Partial breast brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole breast irradiation in older patients. San Antonio Breast Cancer Symposium. 2011;S2-1.
- Jatoi I, Proschan MA. Randomized trials of breast-conserving therapy versus mastectomy for primary breast cancer: A pooled analysis of updated results. Am J Clin Oncol. 2005;28(3):289-294.
- Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med. 1985;312(11):665-673.
- Rutgers EJ, EUSOMA Consensus Group. Quality control in the locoregional treatment of breast cancer. Eur J Cancer. 2001;37(4):447-453.
- Moran MS. Radiation therapy in the locoregional treatment of triple-negative breast cancer. Lancet Oncol. 2015;16(3):e113-22.
- Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol. 2007;25(22):3259-3265.
- Silverstein MJ, Lagios MD. Treatment selection for patients with ductal carcinoma in situ (DCIS) of the breast using the university of southern California/Van nuys (USC/VNPI) prognostic index. Breast J. 2015;21(2):127-132.
- Mamounas EP, Anderson SJ, Dignam JJ, et al. Predictors of locoregional recurrence after neoadjuvant chemotherapy: Results from combined analysis of national surgical adjuvant breast and bowel project B-18 and B-27. J Clin Oncol. 2012;30(32):3960-3966.
- Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med. 2004;351(10):963-970.
- Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: Long-term follow-up of CALGB 9343. J Clin Oncol. 2013;31(19):2382-2387.
- Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM, PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): A randomised controlled trial. Lancet Oncol. 2015;16(3):266-273.
- Gradishar WJ, Anderson BO, Balassanian R, et al. Invasive breast cancer version 1.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2016;14(3):324-354.
- McCormick B, Ottesen RA, Hughes ME, et al. Impact of guideline changes on use or omission of radiation in the elderly with early breast cancer: Practice patterns at national comprehensive cancer network institutions. J Am Coll Surg. 2014;219(4):796-802.
- Soulos PR, Yu JB, Roberts KB, et al. Assessing the impact of a cooperative group trial on breast cancer care in the medicare population. J Clin Oncol. 2012;30(14):1601-1607.
- Kaidar-Person O, Kuten A, Walker GA, Morgan DA. Should radiotherapy be omitted in women age 70 years or older with early breast cancer? J Clin Oncol. 2013;31(36):4569.
- Tsoutsou PG, Jeanneret Sozzi W, Ozsahin M, Delaloye JF, Bourhis J. Radiotherapy options after breast-conserving surgery: How can selection of patients be refined? J Clin Oncol. 2013;31(36):4570-4571.
- Courdi A, Gerard JP. Radiotherapy for elderly patients with breast cancer. J Clin Oncol. 2013;31(36):4571.
- Carlson RW, Moench S, Hurria A, et al. NCCN task force report: Breast cancer in the older woman. J Natl Compr Canc Netw. 2008;6 Suppl 4:S1-25; quiz S26-7.
- Karuturi M, VanderWalde N, Muss H. Approach and management of breast cancer in the elderly. Clin Geriatr Med. 2016;32(1):133-153.
- Spazzapan S, Crivellari D, Bedard P, et al. Therapeutic management of breast cancer in the elderly. Expert Opin Pharmacother. 2011;12(6):945-960.
- Liu FF, Shi W, Done SJ, et al. Identification of a low-risk luminal A breast cancer cohort that may not benefit from breast radiotherapy. J Clin Oncol. 2015;33(18):2035-2040.
- Harris JR. The PRECISION trial (profiling early breast cancer for radiotherapy omission): A phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer. Available at: https://clinicaltrials.gov/ct2/ show/NCT02653755. 2016.
- Konski A, Yu JB, Freedman G, Harrison LB, Johnstone PA. Radiation oncology practice: Adjusting to a new reimbursement model. J Oncol Pract. 2016;12(5):e576-83.
- Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014;383(9917):603-613.
- Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): A randomised controlled equivalence trial. Lancet Oncol. 2013;14(13):1269-1277.