In the present study we found that women more than 70 years old, diagnosed with primary invasive early stage breast cancer, have an inferior relative survival if they are treated with endocrine therapy alone compared with women treated with primary surgery. Further, omission of axillary surgery in clinically node negative patients resulted in a higher risk of regional recurrence, and a tendency to an inferior relative survival. Use of preoperative imaging in this patient group did not seem to result in a better local control.
In a systematic review by the Cochrane Collaboration from 2014, seven randomized trials were identified comparing primary surgery with primary endocrine therapy for elderly women with operable breast cancer. They showed that surgery with adjuvant endocrine therapy resulted in better local control and a tendency to better overall survival than endocrine therapy alone. There was no difference in overall survival in studies comparing surgery alone with endocrine therapy alone . A review from 2017 by Pepping et al however concluded that no difference in overall survival was observed comparing primary endocrine therapy with primary surgery, and they recommended that primary endocrine therapy should be considered for patients with a life expectancy of less than two years and for frail patients especially with low risk tumors . Since these reviews some observational studies have demonstrated that omission of surgery is associated with an inferior overall survival: A Danish observational study by Vogsen et al including 5,856 patients ≥ 70 years diagnosed between 2008 and 2012 showed that omission of surgery among elderly women with early stage breast cancer was associated with an inferior overall survival, and in an interaction analysis this association was significantly more pronounced among women less than 80 years . Interestingly, they further showed that the main reason for deviating from treatment guidelines was patient request . A large British observational study including 23,849 patients diagnosed between 2002–2010 also showed that omission of surgery among elderly women with early stage ER positive breast cancer was associated with a significantly inferior breast cancer specific survival . Our results are in line with these two recent studies. Despite these results it can however be argued that even though we adjust for age and comorbidity using the CCI, some of the effect of primary endocrine therapy on survival can be explained by residual confounding of comorbidity or unmeasurable ‘frailty’. In the SIOG/EUSOMA guidelines from 2012 they recommend that “Primary endocrine therapy should only be offered to elderly individuals with ER-positive tumours who have a short estimated life expectancy (< 2–3 years), who are considered unfit for surgery after optimisation of medical conditions or who refuse surgery. The involvement of a geriatrician is strongly recommended to estimate life expectancy and guide management of reversible comorbidities. It is reasonable to choose tamoxifen or an aromatase inhibitor based on potential side-effects.” . It should be noted, that among all our patients only 9% received primary endocrine therapy alone during the seven-year period from 2000 to 2007. This number is considerably lower than the 15% observed in a Danish study looking at all women ≥ 70 years treated for early stage breast cancer between 2008 and 2012 , and even lower than what has been observed across several European countries . We could, based on these numbers, conclude that undertreatment with primary endocrine therapy alone at our institution is relatively uncommon.
In the present study we found that omission of axillary surgery in clinically node negative patients was associated with a higher risk of regional recurrence. This is in line with a recent meta-analysis . This meta-analysis further showed that omission of axillary surgery in clinically node negative elderly patients did not have an impact on survival, neither overall nor breast cancer specific . It should be noted that the meta-analysis was only based on two RCT’s [19,20]. Given that axillary surgery in previous studies have had no impact on survival, the Choosing Wisely initiative has recommended that ‘Patients ≥ 70 years of age with early stage hormone receptor positive, HER2 negative breast cancer and no palpable axillary lymph nodes can be safely treated without axillary staging’ . This recommendation has however raised some debate among American Breast Cancer Surgeons . Notwithstanding this, a recent American study did show, that since the publication of the Choosing Wisely recommendations, a significant decline in the use of sentinel lymph node biopsies in women older than 70 years has been observed . In our study there was a tendency towards better relative survival among patients who received axillary surgery, although the result was not statistically significant. Besides the effect on regional control, axillary staging is important for the decision on adjuvant treatment. In a study by Tamirisa et al it was demonstrated that elderly breast cancer patients were less likely to receive adjuvant treatment if they did not receive axillary surgery and thus have an inferior survival . This could argue for the use of sentinel lymph node biopsy for staging purposes also among elderly patients.
We were not able to show, that the preoperative omission of mammography and ultrasound in patients treated with breast conserving surgery resulted in a higher risk of local recurrence. It should be noted though, that only 52 patients were registered with local recurrence which should caution any conclusions on whether preoperative imaging can safely bee omitted among these patients. Still, our results do suggest that among elderly women with early stage breast cancer, treated with breast conserving surgery, the omission of preoperative imaging for surgical planning might be a safe solution for certain patients.
The most important limitation to the present study is the risk of confounding, not accounted for. Residual confounding of comorbidity is notably a problem, as it is not unreasonable to assume that the Charlson Comorbidity Index does not capture the full picture of comorbidity and ‘frailty’ among our patients. At worst, all the effect of omitting surgery would be explained by residual comorbidity and frailty. However, if all patients treated primarily with primary endocrine therapy could be regarded as having the same comorbidity and frailty, the difference between patients receiving surgery at a later stage, and the patients who never receive surgery could be regarded as the ‘true’ effect of surgery on survival. As the RR for the first mentioned group is 1.23 and the latter is 2.57, the effect of surgery on survival would still be large. The strengths of our study are that we have very few missing data, and very complete follow-up data on our patients.
In conclusion, our study has demonstrated that treating elderly women with early stage breast cancer with only endocrine therapy is associated with an inferior relative survival, that omitting staging by the sentinel lymph node biopsy results in a higher risk of regional recurrence and a tendency to inferior relative survival, and that omitting preoperative imaging before breast conserving surgery does not result in a higher risk of local recurrence.