In the NEMESI study, a retrospective study which enrolled 1,894 pathological stage I-II breast cancers, 402 pT1a-pT1b tumours were included. A multivariate analysis conducted to evaluate the influence of patient and tumour characteristics on the decision to administer or not adjuvant chemotherapy in pT1a-pT1b breast cancers, showed that younger age, grading G3, high proliferative index, ER-negative status and HER2-positive status were significantly associated with the decision to administer adjuvant chemotherapy. In the patients treated with adjuvant chemotherapy, an anthracycline-based regimen was administered in 83.5% (anthracycline without taxane in 59.1% and anthracycline with taxane in 24.4%) while a CMF-like regimen was administered in only 13.38%. In our study compliance to adjuvant chemotherapy was high (82.67% of patients received 4–6 planned cycles) and the definitive interruption of chemotherapy occurred in only eight patients.
The adjuvant systemic therapy of small tumour size with no axillary lymph node involvement is controversial. The risk of relapse is related to stage of tumour (tumour size and lymph node status) and to biological characteristics. Therefore, in pT1a-pT1b tumours, which are pN0 in 82%–85% of the cases, the biological markers are utilised during treatment decision-making. In our study, the variables significantly associated with the decision to administer adjuvant chemotherapy in pT1a-pT1b breast cancers were younger age and the biological markers associated with a poor prognosis (grading G3, high proliferative index, ER-negative status and HER2-positive status) [14, 16, 21–28], and also predictive of chemoresponsivity in the neoadjuvant setting.
Several changes in indication to adjuvant systemic therapy occurred for patients with node-negative tumours ≤ 1 cm in size according to 1998–2007 St Gallen Consensus Conference guidelines. In the 1998 St Gallen Consensus Conference the population with <10% of relapse was not considered for adjuvant systemic therapy . The 2005 Consensus Conference made a fundamental change in the algorithm for the selection of adjuvant systemic therapy for early breast cancer, considering first endocrine responsiveness and then the risk of relapse. The risk allocation of tumours below 1 cm in size and negative nodes remained still controversial . The 2007 St Gallen Consensus Conference  utilised the biological factors associated to worse prognosis, considered singularly or together, to identify the endocrine non responsive tumours suitable for only adjuvant chemotherapy, and to identify the incompletely or highly endocrine responsive tumours suitable, according to risk of relapse, for addition of adjuvant chemotherapy to hormonal therapy, irrespective of tumour size. However, some but not all panel members viewed pT≤1 cm tumours with node-negative disease as representing low risk even if higher grade and/or younger age. The NCCN Practice Guidelines 2007 http://www.nccn.org recommended adjuvant chemotherapy only in tumours between 6 mm and 10 mm without metastases in lymph nodes (pT1b pN0): in ER-negative pT1b pN0 (both HER2-negative and HER2-positive) and, in addition to hormonal therapy, in ER positive pT1b pN0 moderate/poorly differentiated or with unfavourable features (both HER2-negative and HER2-positive).
We report that an anthracycline-based regimen was administered in 83.5% of patients (anthracycline without taxane in 59.1% and anthracycline with taxane in 24.4%) while CMF-like anthracycline-regimens (without or with taxane) highlights that if the decision was to administer chemotherapy, the most active regimen was selected, also in small breast cancers. This trend was observed also in all patients with stage I-II breast cancer enrolled in the NEMESI study  as well as in the NEMESI subgroup of triple-negative tumours .
Our study has some limits. Although the majority of pT1a-pT1b breast cancers had favourable prognostic factors, as reported in other retrospective studies [7–11], adjuvant chemotherapy was delivered in 31.59% of patients. This percentage is considerable but may not reflect the clinical practice and must be evaluated considering both the eligibility criteria of NEMESI (the patients enrolled must have received at least one cycle of adjuvant chemotherapy and/or adjuvant hormonal therapy) and the requirement that each centre had to collect the data of at least 33% of the patients undergoing adjuvant chemotherapy. It is necessary consider this limit also when we reported that 36 out of 49 patients with HER2-positive small breast cancer were treated with adjuvant chemotherapy (73.46%). Thirty out of these 36 HER2-positive patients were pN0 and in these patients the choice of administered chemotherapy was independent of other patient and tumour characteristics and based only on HER2-positivity, considered a poor prognostic factor [22–24], as well confirmed by recent studies [25–28]. Adjuvant trastuzumab was administered in 30 of 36 patients who received chemotherapy. HER2-positivity is a predictive factor of trastuzumab response, but although five out of six randomised phase III trials reported marked benefit of adjuvant trastuzumab for disease-free and overall survival (with reduction of recurrence and mortality by 20-40%) [34–38], there are no data on trastuzumab in pT1a-pT1b HER2-positive breast cancer. On the other hand, there is indirect evidence. In the BCIRG006 and HERA subgroup analyses adjuvant trastuzumab did not result in different rates of risk reduction among HER2-positive breast cancers in function of nodal status or tumour size [35, 39, 40]. More data supporting the use of adjuvant trastuzumab in small node-negative HER2-positive breast cancer emerged from three recently reported retrospective investigations. In a French multicenter series from 2002 to 2008, 97 patients with pT1a,b pN0 HER2-positive tumours were identified. Forty-one patients (42%) had been treated with adjuvant trastuzumab-based therapy with (n = 38) or without (n = 3) chemotherapy . The decision to administer adjuvant trastuzumab was significantly associated with a negative hormonal receptor status, a high Eltson-Ellis grade, a moderate/high mitotic index, and the date of the diagnosis (before or after the HERA results were released). With a median follow-up of 29 months, there were no recurrences in patients treated with trastuzumab-based therapy while 5 of 56 patients who did not receive trastuzumab had developed a recurrence. Another single-institution retrospective study included 485 women with node-negative, HER2-positive tumours ≤2 cm treated in the pre- (2002–2004) and post- (2005–2008) trastuzumab era . Events of disease recurrence were more frequent in the pre-trastuzumab group as compared with the post-trastuzumab group. A third study reported the breast cancer specific 5-year survival of HER2-positive pT1a and pT1b pN0 breast cancer in 20,188 patients identified in the California Cancer Registry . It was significantly shorter among HER2-positive breast cancer compared to HER2-negative patients (p = 0.0001) in the 2000–2004 era, while there was no difference in the 2005–2007 era, after the introduction in clinical practice of adjuvant trastuzumab.
The 2007 St Gallen Consensus Conference did not recommend adjuvant trastuzumab in women with a primary tumour < 1 cm in size and with no axillary node involvement , and also the 2007 NCCN Guidelines did not indicate trastuzumab in tumours <1 cm. On the other hand, the more recent version of the NCCN Guidelines 2011 (v.2.2011) recommend the use of adjuvant trastuzumab in women with node-negative tumours (both HR-positive and HR-negative) that are 0.6 to 1.0 cm as category 2A recommendation, because patients with tumours 1 cm or smaller and node negative were not consistently included in the available clinical trials. The majority of the Panel members of the 2011 St Gallen Consensus Conference were willing to extended adjuvant trastuzumab to patients with pT1b, but not pT1a pN0 disease .
Moreover, hormonal therapy, planned in 351 patients out of 354 hormonal receptor-positive pT1a-pT1b tumours, was administered in 346 patients (97.7%). These data are very different from those reported by an audit of clinical practice in Italy conducted in March 2000 regarding adjuvant systemic therapies prescribed for breast cancer. In this audit it resulted that endocrine therapy was not prescribed in 102 out of 541 patients (19%) with endocrine-responsive disease .