A Prospective Cohort Study Evaluating Risk of Local Recurrence Following Breast Conserving Surgery and Endocrine Therapy in Low Risk Luminal A Breast Cancer

This is a multicentre, single-arm prospective cohort study evaluating risk of ipsilateral breast tumour recurrence(IBTR) following breast conserving surgery (BCS) in a group of women postulated to be at low risk for recurrence. Women with luminal A breast cancer determined by immunohistochemical(IHC) and other low risk clinical testing (see below) will be treated with endocrine therapy (tamoxifen or aromatase inhibitor) for five years and will not be treated with breast irradiation (BI). Subjects will be followed for 10 years and will be assessed for recurrent disease, new primary cancer and survival.

The independent prognostic ability of the luminal A subtype has been demonstrated in two retrospective analyses of prospective trials and suggests that luminal A combined with other known clinical prognostic factors could be used to select patients treated with BCS at very low risk for IBTR who could avoid BI. Given that using intrinsic subtyping combined with other clinical factors to identify women who could avoid BI would be a major change in clinical practice, we propose that a prospective study is necessary to confirm that such an approach can accurately identify a group of women at very low risk for IBTR following BCS.

We anticipate that the risk of IBTR in the low risk group is likely to be lower than that observed in previous trials (predicted to be \< 5% at 5 years and \< 10% at 10 years) for several reasons: first, our selection criteria (node negative, luminal A, \> or = 55 years, tumours \< or = 2cm, excision margin \> or = 1mm post-BCS, absence of lobular cancers, extensive intraductal component and lymphovascular invasion) are more restrictive than in previous trials and second, the risks of IBTR are steadily decreasing over time due to improvements in mammographic screening, pre-op staging, tumour localization, and surgical practice. The expected low failure rates are unlikely to warrant the use of radiation.

A prospective cohort study was identified as the most appropriate and efficient design as our primary hypothesis is that a group of patients at very low risk of IBTR can be identified. A randomized trial could address the effectiveness of radiation in such a cohort of patients, but would require a much larger sample size to detect very small differences, which would not be clinically meaningful. During the conduct of this trial it is anticipated that patients who do not meet study criteria or who decline study enrollment, will continue to receive BI after BCS.

Eligibility Criteria:
Inclusion Criteria:

1. Female patient \> or = 55 years of age with a new diagnosis of invasive carcinoma of the breast (ductal, tubular or mucinous only) with primary tumour \< or =2cm on microscopic exam, with no evidence of metastatic disease;
2. ER positive (\> or =1%) and PR positive (\>20%) and HER2 negative (Immunohistochemical (IHC) or In Situ Hybridization (ISH) approach);
3. Treated by BCS with microscopically clear resection margins \> or = 1mm for invasive and non-invasive disease or no residual disease on re-excision;
4. Negative axillary node involvement determined by sentinel node biopsy or axillary node dissection.

Exclusion Criteria:

1. Clinical or pathological evidence of T4 disease (i.e. extension to chest wall, skin involvement, peau d'orange, or inflammatory breast cancer).
2. Multifocal or multicentric disease.
3. Evidence of an extensive intraductal component (defined as a tumour that is composed of 25% or more of DCIS and the DCIS extends beyond the gross dimensions of the tumour), or disease limited to micro invasion only.
4. Grade 3 histology for invasive disease
5. Evidence of lymphovascular invasion.
6. Evidence of disease on pre-operative mammogram, aside from primary cancer treated by breast conserving surgery.
7. Bilateral malignancy of the breast (synchronous or metachronous).
8. Known BRCA 1 or 2 mutations.
9. History of non-breast cancer malignancies if not disease free for \> 5 years and considered low risk of recurrence with the exception of treated carcinoma in-situ of the cervix, endometrium or colon, melanoma in-situ and basal or squamous cell carcinoma of the skin.
10. Serious non-malignant disease associated with a life expectancy \< 10 years.
11. Inability to be treated with or to tolerate endocrine therapy.
12. Psychiatric or addictive disorder, which would preclude obtaining informed consent or adherence to protocol.
13. Geographic inaccessibility for follow-up.
14. Inability to understand or unable to provide written informed consent.
15. Inability to be registered on study within 12 weeks of the last surgical procedure on the breast.
16. Central testing for Ki67 \> 13.25% consistent with the luminal B subtype