In our real-life retrospective cohort, with a mean follow-up of 10-years, patients with T1a/bN0 BC and RS > 25, did not show improved iDFS with aCT compared to those who did not receive aCT. To our knowledge, this is the largest cohort examining this question [2, 8–9].
We chose RS > 25 as the threshold for benefit from chemotherapy in patients without lymph node involvement based on TAILORx results [4], and the NSABP B-20 results when HER2 positive patients were excluded [3]. Furthermore, a prior published CHS registry analysis could not identify improved outcomes with aCT in patients with RS RS 26–30 [10]. However, we can not exclude benefit with a higher RS.
In our patient cohort three parameters were associated with aCT administration: age, low Charlson’s comorbidity score and RS ≥ 31. This represents the preferences of Oncologists in real-life when considering aCT in T1a/bN0 BC. Younger age was found to be associated with aCT administration in prior analysis of the CHS registry (Charlson’s comorbidity was not evaluated in the study) [10].
Although, approximately 20% of newly diagnosed breast tumors are in the T1a/bN0 stage [5], prospective data on the benefits of aCT in this subgroup is lacking. Perhaps, due to limited adoption of aCT within this subgroup as reflected in the recent St. Gallen recommendations where approximately 90% of expert panelists [11] voted against providing aCT for tumors < 0.8 cm N0 despite a high genomic assay result. Interestingly, same experts were more inclined (up to 40%) recommending aCT for slightly larger, 0.8-1cm tumors.
In our cohort, there were 12.2% iDFS events and 4.5% distant recurrences events. Our findings are consistent with the MINDACT study that showed excellent disease-free survival and distant metastasis-free survival in patients with breast cancer of low-clinical (tumors ≤ 1cm N0) and high-genomic risk who did not receive aCT [12–13].
Interestingly, we noticed that the mean time to an iDFS or to a distant recurrence event exceeded 171.5 and 186.2 months (Fig. 2, 3), respectively, emphasizing the inherent risk for late-recurrence of ER+/HER2- small tumors which is not predicted by the current RS assay [14].
The strength of our study lies in the highly selective study population, consisting of small N0 tumors with high genomic risk and the lengthy follow-up duration (median of ten years). To our knowledge, this is the largest breast cancer real-life cohort that examined benefit from aCT in T1a/bN0 BC. Very small tumors are usually under-represented in clinical trials, e.g. in the TAILORx study only 13% of patients had tumors 1cm or smaller (tumor 0.5 > were excluded) [4] and in the NSABP B-20 trial (excluding HER2 positive by RT-PCR) only 14.9% had such tumors [3].
In addition, we used the CHS registry, a well-established registry reflecting real- world experience that was used as a validation cohort to develop the RSclin tool, which aimed to individualize prognosis and prediction of chemotherapy benefit [14]. The registry served as a basis for many published BC manuscripts [10, 14].
Our study has several limitations. The primary limitation is its retrospective and uncontrolled nature, leading to an imbalance between characteristics of patients who received aCT and those who did not, although the use of PS-matching addressed this limitation. Another significant limitation is the low number of events observed, consistent with the prognosis of patients with low-clinical risk and high-genomic risk in the MINDACT trial [12].
Another study constraint arises from the selection bias inherent in the study cohort, comprised of patients selected by their treating physician to undergo 21- gene expression assay testing. Ordering genomic testing in Israel is at the discretion of the breast surgeon or treating oncologist and not limited by tumor size. Therefore, the study cohort may not represent the entire T1a/bN0 population and represents patients to whom aCT was considered, younger patients or those with a more luminal B-like phenotype BC (defined by grade 2–3, lower progesterone receptor expression and a higher cell proliferation) associated with an inferior outcome. We believe this limitation did not adversely affect the study results, because the absence of benefit from aCT in these higher-risk tumors would probably extend to a lack of benefit in lower clinical-risk tumors with a more luminal A-like phenotype.
Another limitation, is the small subgroup of T1a tumors (8/156 patients), especially those treated with aCT (2/8 patients) prevent drawing conclusions regarding any benefit from aCT in this subgroup.
In summary, within our retrospective study cohort, aCT did not improve outcomes of patients with T1a/bN0 HR+/HER2- BC with RS > 25, suggesting, a RS > 25 is not predictive of benefit from aCT in our study. This low number of events observed in our study supports the good prognosis of these patients.
However, prospective trials are needed to identify at diagnosis those few patients who later experience distant recurrence, possibly by evaluating RS ≥ 31 threshold. Another possibility, is integrating clinicopathologic biomarkers with the RS, that could potentially lead to more accurate identification of patients with small tumors at high- risk for recurrence, allowing others to avoid unnecessary aCT. This becomes increasingly important as more patients are diagnosed with T1a/bN0 tumors through routine BC screening.