The omission of radiotherapy after breast-conserving surgery in older women with hormone receptor-positive, node-negative early breast cancer increases the risk of local recurrence: phase 3 randomized trial showed a 10-year cumulative incidence of local recurrence of 9.5% in the no-radiotherapy group compared to 0.9% in the radiotherapy group.
Despite the increased local recurrence, the omission of radiotherapy did not significantly affect distant recurrence or overall survival.
The 10-year overall survival rates were nearly identical between the groups receiving and not receiving radiotherapy.
Gudelines suggest that radiotherapy can be omitted in older women (≥65 years) with low-risk, hormone receptor-positive early breast cancer who are receiving adjuvant endocrine therapy.
Omitting radiotherapy can improve quality of life, reduce treatment-related side effects, such as cardiac events and second cancers, and avoid the inconvenience and cost associated with radiotherapy.
The decision to omit radiotherapy should be individualized based on patient age, tumor characteristics, and patient preferences.
Molecular subtyping and clinicopathologic factors can help identify patients at low risk for local recurrence who may safely omit radiotherapy.
Radiation therapy (RT) after breast conserving surgery decreases the risks of local recurrence and breast cancer mortality in the multidisciplinary management of patients with breast cancer.
However, breast cancer is a heterogeneous disease, and the absolute benefit of post-operative RT in individual patients varies substantially.
The majority of patients with early breast cancer continue to be routinely treated with RT after breast conserving surgery.
This approach represents over-treatment for a substantial proportion of the patients.
Benefit of radiotherapy (RT) after breast conserving surgery in individual patients varies.
The routine use of post-operative RT may represent over-treatment for some patients.
Clinical trials are not consistently successful in identifying low-risk patients using clinical-pathologic factors.
Breast cancer has become the leading cause of global cancer incidence in 2020, with 2.3 million new cases, representing 11.7 % of all cancer cases.
In women, breast cancer accounts for one in four cancer cases, ranking first for incidence in the vast majority of countries.
Radiation therapy (RT) after breast conserving surgery is integral to contemporary multidisciplinary management of patients with invasive breast cancer to improve local tumor control and decrease breast cancer mortality.
Post-operative RT halves the recurrence rate and reduces the breast cancer death rate by a sixth.
The importance of personalizing care of patients with early breast cancer is further underscored by the falling recurrence rates with or without RT over the last 20 years due to advances in multidisciplinary breast cancer management.
An Early Breast Cancer Trialists Collaborative Group (EBCTCG) meta-analysis showed that a reduction in 5-year local recurrence rate was associated with a decrease in 15-year breast cancer mortality.
However, a more recent meta-analysis showed that a 7 % decrease in 10-year overall (local and distant) recurrence risk was associated with a 0.1 % reduction in 15-year breast cancer mortality.
RT morbidity: modern techniques may reduce cardiac irradiation, R has been shown to be associated with increased cardiac mortality that nullified the decrease in breast cancer deaths
A randomized trial reported a higher incidence of breast pain, fibrosis and edema, and poorer cosmetic result in the RT group than the no RT group.
There is a small but definite risk of potentially life-threatening radiation-induced sarcoma.
It is recognized that selected patients with early breast cancer are unlikely to derive benefits from RT after breast conserving surgery.
Randomized trials have been conducted to define these low-risk patient subgroups: The majority of the trial patients were aged over 50 years with stage I hormone receptor-positive and non-high grade early breast cancer.
High local recurrence rates after breast conserving surgery were observed in the earlier randomized trials examining omission of post-operative RT.
More recent trials confirmed the established effect of RT in decreasing local recurrence rates in low-risk patients defined using conventional clinical-pathologic characteristics, these trials also reported a lower local recurrence rate of approximately 10 % at 10 years and no significant adverse survival impact in the no-RT groups.
The drivers of this this improvement in local control without post-operative RT might be attributed primarily to advances in multidisciplinary care including improvements in breast imaging, surgical guidelines, and pathologic techniques in excision margin assessment.
Adjuvant endocrine therapy, also contributeds to local tumor control.
Trials examining the omission of RT after breast conserving surgery in selected older patients with early breast cancer, the Cancer and Leukaemia Group (CALGB) 9343 and Postoperative Radiotherapy in Minimum-Risk Elderly II (PRIME II) trials
The CALGB 9343 trial randomized women ≥70 years of age with clinical stage I, estrogen receptor (ER)-positive breast cancer treated by breast conserving surgery to receive tamoxifen and RT or tamoxifen alone.
At a median follow-up of 12.6 years, RT decreased the 10-year local-regional recurrence rate from 10 % to 2 % without affecting the breast preservation rate.
This improvement in local control did not translate into an advantage in overall survival, distant disease-free survival, or breast preservation.
The 10-year overall survival was 67 % in the RT group and 66 % in the no-RT group.
Non-breast cancer causes accounted for 93.7 % of the deaths.
The 10-year probability of not undergoing mastectomy was 98 % in the RT group and 96 % in the no-RT group.
Findings support the clinical practice that most patients who develop local recurrence after breast conserving surgery without RT could be successfully salvaged by further breast conserving surgery, usually followed by RT.
The PRIME II trial involved patients aged ≥65 years who had breast conserving surgery and adjuvant tamoxifen for early breast cancer considered to be low-risk (hormone receptor–positive, node-negative, T1 or T2 primary breast cancer ≤3 cm in the largest dimension): At a median follow-up of 9.1 years, the cumulative incidence of local recurrence within 10 years was 0.9 % with RT and 9.5 % without RT.
The 10-year overall survival was almost identical in the two groups, at 80.7 % with RT and 80.8 % without RT, and the corresponding breast cancer specific-survival estimates were 97.9 % and 97.4 %.
Consistent with CALGB 9343 trial, non-breast cancer causes accounted for 93.4 % of the deaths.
Guidelines that omission of RT after breast conserving surgery and endocrine therapy may be considered in older patients with a small, hormone receptor-positive and node-negative early breast cancer.
Guidelines for treatment of early breast cancer supports omission of RT in patients with stage I, ER-positive breast cancer who are likely to be adherent with adjuvant endocrine therapy, and patients with shorter life expectancies
The impact of guidelines on changing practice has been minimal.
Immunohistochemical (IHC) panels including ER, progesterone receptor (PgR), human epidermal growth factor receptor-2 (HER-2) and Ki67 have been used as surrogates for molecular subtyping.
Studies evaluating IHC-defined molecular subtypes found that luminal A tumors (ER or PR positive, HER-2 negative, Ki67 < 14 %) had the lowest local recurrence rate compared to other subtypes.
The 21-gene Oncotype DX Recurrence Score is an approved diagnostic test to guide adjuvant endocrine and chemotherapy decision in patients who are postmenopausal or age >50 years with ER-positive, HER2-negative breast cancer that is node-negative or with 1–3 positive nodes
Recurrence Score is significantly associated with local recurrence risk.
The POLAR genomic signature may have the potential to identify patients with a sufficiently low risk of local recurrence to guide RT omission.
Genomic signatures designed primarily for estimation of the risk of distant relapse suggest that biologic features driving distant relapse may also be predictive of local recurrence.
Systemic therapy has an important role in local tumor control, and may confound the ability of genomic assays to guide RT decisions
Prospective clinical trials are in progress to evaluate genomic assays for precise determination of local recurrence risk, and identify patients with biologically low-risk disease for omission of post-operative RT.
LUMINA, a prospective multicenter cohort study evaluated the risk of local recurrence following breast conserving surgery and endocrine therapy in 501 women aged ≥55 years with T1N0, grade 1–2, luminal A breast cancer (defined as ER ≥1 %, PR >20 %, HER2-negative and Ki67 ≤13.25 %) which was excised with ≥1 mm excision margins.
Patients were assigned to not receive RT.
Results have showed a low incidence of 5-year local recurrence (2.3 %,) to support the study conclusion that RT may be omitted in patients who meet study criteria.
IDEA is a prospective multicentre single-arm study examining whether addition of a multigene assay to conventional clinical-pathologic factors could identify a subgroup of younger postmenopausal patients with low recurrence rates after breast conserving surgery and endocrine therapy without post-operative RT.
At a median follow-up of 5.21 years, in the 200 patients with pT1N0, ER and PR positive, HER2-negative breast cancer that was excised with margins ≥2 mm and had an Oncotype DX 21-gene recurrence score ≤18, the 5-year freedom from any recurrence was 99 % (95 % confidence interval, 96–100 %) and the crude rates of ipsilateral breast events for patients aged 50–59 years and 60–69 years were 3.3 % and 3.6 %, respectively.
The study included few patients with lymphovascular invasion (8 %) and poorly differentiated tumour grade (3 %). Thus, the study was underpowered to detect differences in local recurrence rates between patients with and without these adverse tumour characteristics. The endocrine therapy compliance rate of IDEA was comparable to LUMINA at 85 %.
The low recurrence rate underscores the importance of tumor biology in improving selection of low-risk patients for omission of post-operative RT.
While endocrine therapy is generally well-tolerated, adverse effects including fatigue, hot flushes, sexual dysfunction, weight gain and musculoskeletal symptoms may limit treatment adherence in some patients.
The PRIME II trial showed that non-adherence to adjuvant endocrine therapy, often due to treatment related toxicity, resulted in an increased local recurrence rate in patients who did not have adequate adherence: <80 % adherence was associated with significantly decreased benefit from adjuvant endocrine therapy
In randomized trials showing comparable efficacy and toxicity of the 5-fraction ultra-hypofractionated whole breast RT and accelerated partial breast RT, which reduce patient burden compared to the more protracted course of whole breast RT has led to the contention that a short course of RT may be an alternative to endocrine therapy in selected patients.
Exqclusive Endocrine Therapy or Radiation Therapy for Women Aged ≥70 Years With Luminal A study-like Early Stage Breast Cancer (EUROPA), a randomized phase 3 trial is comparing health-related quality of life of patients treated with partial breast RT alone versus endocrine therapy alone after breast conserving surgery.
Genomic signatures such as POLAR may be of particular relevance in identifying low-risk patients who could safely omit both RT and endocrine therapy after breast conserving surgery as it was developed and validated in patients who were not treated with endocrine therapy.
Patients categorized as POLAR low-risk had a low 10-year local recurrence rate of 6 % without RT or endocrine therapy.
The majority of patients with early breast cancer continue to be routinely treated with RT after breast conserving surgery.
This approach represents over-treatment for a substantial proportion of the patients, and comes at a price in terms of unnecessary treatment toxicity, financial costs, logistical challenges, and ineffective use of sparse RT resources.
Trials of patients with intermediate risk breast cancer who underwent mastectomy have shown no significant difference in 10 years survival between those who receive post mastectomy radiotherapy to the chest wall, and those who did not.
These findings were different than the Early Breast Cancer Trialists’ Collaborative group in 2014, which showed their postmastectomy chestwall radiation was associated with significantly fewer first local regional recurrences than no chest wall radiation as well as breast cancer specific survival that was 8.1 percentage points higher in 20 years in patients with positive lymph nodes.
These trials however were initiated with systemic treatments that are presently regarded as outdated.
In the BIG/SUPREMO trial of patients with intermediate risk breast cancer underwent mastectomy, there was no significant difference in 10 years in the survival between those who receive post mastectomy radiotherapy to the chestwall and those who did not: the incidence of chestwall recurrence was 1.4 percentage points with 1.1% with the radiation versus 2.5% with no chest wall radiation.