Skip to main content

Adjuvant chemotherapy of pT1a and pT1b breast carcinoma: results from the NEMESI study

Abstract

Background

The prognosis of pT1a-pT1b breast cancer (BC) used to be considered very good, with a 10-y RFS of 90%. However, some retrospective studies reported a 10-y RFS of 81%–86% and suggested benefit from adjuvant systemic therapy.

Methods

To evaluate the variables that determined the choice of adjuvant chemotherapy and the type of chemotherapy delivered in pT1a-pT1b BC, we analysed the small tumours enrolled in the NEMESI study.

Results

Out of 1,894 patients with pathological stage I-II BC enrolled in NEMESI, 402 (21.2%) were pT1a-pT1b. Adjuvant chemotherapy was delivered in 127/402 (31.59%). Younger age, grading G3, high proliferative index, ER-negative and HER2-positive status were significantly associated with the decision to administer adjuvant chemotherapy. An anthracycline without taxane regimen was administered in 59.1% of patients, anthracycline with taxane in 24.4%, a CMF-like regimen in 14.2% and taxane in 2.4%. Adjuvant chemotherapy was administered in 88.4% triple-negative and 73.46% HER2-positive pT1a-pT1b BC. Adjuvant trastuzumab was delivered in 30/49 HER2-positive BC (61.2%).

Conclusions

Adjuvant chemotherapy was delivered in 31.59% T1a-pT1b BC treated at 63 Italian oncological centres from January 2008 to June 2008. The choice to deliver chemotherapy was based on biological prognostic factors. Anthracycline-based chemotherapy was administered in 83.5% patients.

Peer Review reports

Background

Breast cancer is the first cause of tumour-related death in women in Italy [15]. Moreover, the incidence of breast cancer has been increasing over the last 15 years in industrialised countries as the result of both Rx-mammographic screening programs [15] and advances in breast cancer awareness. The increase in incidence due to mammography screening has been due to the increase in small T1 cancers [5, 6]. In Italy, the pT1-pT1b incidence was 9.6% in 1988–1990 and 21.4% in 2005–2007 (AIRTUM, data not published; http://www.registri-tumori.it): these tumours were pN0 in 82%–85% of the cases.

The prognosis of these small cancers used to be considered very good, with a relapse-free survival rate at 10 years without adjuvant therapy of 90% [711]. However, some retrospective studies have reported a worse outcome, with 81%–86% of relapse-free survival at 10 years [1215]. Furthermore, Fisher et al. [16] reporting survival data on 1,259 patients with pT1a-pT1b N0 breast cancer enrolled in 5 randomised NSABP trials, suggested that these patients could have benefited from adjuvant systemic therapy. Given that there is an ongoing debate on the adjuvant treatment of these tumours, we analysed the patients with pT1a-pT1b breast cancer enrolled in the NEMESI study, a retrospective observational study conducted in 2009 at 63 Italian oncological centres. We evaluated the adjuvant systemic treatments delivered, the variables which determined the choice to administer chemotherapy, the type of chemotherapy delivered and compliance with chemotherapy in pT1a-pT1b breast cancers.

Methods

Study design

NEMESI is a retrospective observational study conducted at 63 Italian oncological centres. The centres were extracted from a database of 319 oncological centres reported in the census of the Italian Association Medical Oncology (AIOM) [17] and stratified by geographical area (Northern, Central, Southern Italy, including Sicily and Sardinia) and kind of institution (public hospital, university hospital, research institute, private hospital, other), since these factors were considered to have an important impact on compliance with guidelines.

The endpoints of the NEMESI study were: to describe the adjuvant systemic treatments delivered in pathological stage I-II breast cancer, to evaluate the variables which determined the choice of adjuvant chemotherapy and the type of chemotherapy, to evaluate compliance with the treatment administered, and to compare the practice observed in Italian clinical settings with that proposed by international guidelines.

Criteria of eligibility were: women age ≥18 years; histological diagnosis of invasive breast cancer stage I-II (AJCC version VI) [18] who underwent surgery; at least one cycle of adjuvant chemotherapy and/or adjuvant hormonal therapy; availability of the following local staging and biological parameters: pT, pN, grading, estrogen receptor (ER), progesterone receptor (PgR), proliferative index (Ki67 or MIB-1), HER2. Candidates for adjuvant therapy with trastuzumab and/or radiotherapy on residual breast or thoracic wall and/or regional supraclavicular and/or internal breast lymph node stations were also eligible. Exclusion criteria were: neo-adjuvant chemotherapy and/or hormonal therapy, locally advanced and/or metastatic (stage III-IV) breast cancer, and in-situ carcinoma. Data were retrospectively retrieved by each site from the patients’ clinical records.

The protocol was reviewed by the independent ethics committee of the coordinating centre and notification of the study was sent to the ethics committees of each participating centre [19]. The protocol complied with the recommendations of the 18th World Health Congress (Helsinki, 1964) [20].

Sample size determination and data collection

The study aimed at collecting data from the clinical records of not less than 1,300 and not more than 1,500 patients attending at least 50 oncologic centres. These figures correspond to 3.6% and 4.2% respectively of the new cases of early stage breast cancer recorded each year in Italy (about 40,000 cases, 90% of which are early stage), and 12.5% of the Italian oncologic sites (about 400 throughout Italy).

Each centre was requested to collect, within December 2009, the data of a minimum of ten and a maximum of 30 consecutive patients with early breast cancer between 1 January 2008 and 30 June 2008; with the only requirement being to collect the data of at least 33% of the patients undergoing adjuvant chemotherapy. This requirement was mandatory because the primary objective of the study was not to assess how many patients received adjuvant chemotherapy within that period but to identify the biological, staging and demographic parameters that determined: (i) whether adjuvant chemotherapy would be prescribed, and (ii) the type and schedule of chemotherapy selected. To ensure anonymity, the percentage of patients enrolled in the study could not exceed 50% of the patients attending the centre during the study period. According to the study protocol, central revision of all tissue samples was not done.

The data, collected on an electronic clinical report form, were submitted to automatic checks to assess completeness, correctness and internal coherence. Possible discrepancies or otherwise unreliable data were submitted to the investigator in the form of queries for clarification and/or resolution.

Variables evaluated

In the NEMESI study patient and tumour characteristics, type of local-regional treatment and adjuvant systemic therapy, and compliance to chemotherapy were evaluated. In this NEMESI sub-study, only the pT1a-pT1b breast cancers were analysed. We evaluated: patient characteristics (age class, menopausal status), stage according to the TNM AJCC version VI classification, bio-pathological characteristics of the primitive tumour (histology, vascular invasion, grading, ER, PgR, HER2, and the proliferative index), type of surgery, adjuvant systemic therapy (chemotherapy, hormonal therapy, trastuzumab, concurrent adjuvant treatment with other experimental drugs), the variables associated with choice of administered adjuvant chemotherapy and compliance to chemotherapy. Moreover, in HER2-positive small tumours the variables associated with choice of administered adjuvant chemotherapy and trastuzamab were analysed.

Statistical methods

In this survey 402 patients were examined with pT1a-pT1b breast tumour stage from a total of 1,894 patients enrolled in the NEMESI clinical study. The analysis was performed considering not only the reference population but also various subgroups decided in accordance with different analysis purposes. For most of these groups both descriptive analysis and inferential analysis were performed. As a descriptive analysis, continuous variables were summarised using descriptive statistics, including number of subjects: mean, standard deviation, and median, while for categorical variables summaries included counts of subjects and percentages. Pearson’s Chi-Square (χ2) test was performed in order to evaluate whether the frequency distribution of certain events observed in a sample (for example variables as age, menopausal status, grading, ER status) is consistent with their theoretical distributions. Chi-Square test for Specified Proportions was used to compare, in one way frequency tables, the homogeneity proportion between the general population (pathological stage I-II with the exclusion of pT1a, pT1b, considered as a reference distribution) and the distribution of the same variables in the subgroup of pT1a-pT1b patients. For both tests, the significance level used was equal to p = 0.05.

Multivariate logistic regression analysis was performed to assess the relationship between clinical and demographic variables and the type and treatment schedule of adjuvant chemotherapy administered with many covariates: age class, menopausal status, vascular invasion, ECOG performance status, type of surgery, TNM stage, ER, PgR, HER2 status, proliferative index. The logistic model contained only categorical variables. The continuous variables (e.g. proliferative index, ER, PgR, HER2) were categorized in different classes according to international indications.

The selection of variables to include in the model was defined using the stepwise procedure with a significant level of p = 0.05 to include variables in the model. In the logistic model the odds ratio estimates and their 95% confidence limits were also calculated. All statistical analysis was performed using SAS (Statistical Analysis System, SAS Institute Inc., Cary, NC, USA) version 9.1.3 for Windows.

Results

In the NEMESI study 1,894 patients with pathological stage I-II breast cancer were enrolled by 63 Italian centres. Out of 1,894 cases included in this survey, 402 (21.2%) were pT1a-pT1b breast cancers. Patient and tumour characteristics are reported in Tables 1 and 2; no considerable relevant differences were observed between pT1a-pT1b breast cancers. Conservative breast surgery and node sentinel biopsy were performed in 86% and in 79.3% of pT1a-pT1b tumours, respectively (Table 1). The majority of the tumours were pN0 (78.8%) and showed G1-G2 grading (80.6%), absence of vascular invasion (67.5%), low proliferative index (71.8%), hormonal status positive (89.7%), HER2-status negative (88.12%) (Table 2). Patients and tumour characteristics of 402 pT1a-pT1b breast cancers were compared to 1,492 ≥pT1c tumours of NEMESI study (Table 3). The following variables were distributed in a statistically different manner between the groups: menopausal status (p = 0.015), conservative surgery (p <0.0001), grading (p < 0.0001), proliferative index (p < 0.0001), ER status (p = 0.02), hormonal receptor status (p = 0.006) and HER2 status (p = 0.009). Analysing the different categories of the statistically significant variables, it was observed that in 402 pT1a-pT1b breast cancers compared to other 1,492 cases, there were higher percentages of: postmenopausal patients (72.8% vs 68%; p = 0.05), tumours that underwent conservative surgery (86.7% vs 72.5%; p = 0.005) and sentinel node biopsies (79.4% vs 60.5%; p < 0.0001), tumours with grading G1 (25.1% vs 8.0%; p < 0.0001) and with a low proliferative index (70.6% vs 47.4%; p <0.0001). In the pT1a-pT1b tumours a lower incidence of prognostic biological factors associated with poor prognosis was observed: ER-negative status (12.7% vs 18.5%; p = 0.01), ER and PgR negative status (11.9% vs 17.9%; p = 0.01), and HER2-positive status (12.2% vs 18.7%; p = 0.006). These small breast cancers (≤ 1 cm) showed a higher percentage of pN0 (79.4% vs 56%; p <0.0001) compared to 1,492 ≥pT1c tumours of the NEMESI study.

Table 1 Patient characteristics and treatment
Table 2 Biopathological characteristics
Table 3 Patient and tumour characteristics of pT1a-pT1b tumours vs other stage I-II tumours in the NEMESI study

Adjuvant chemotherapy was delivered in 127 out of 402 patients (31.59%) with pT1a-pT1b breast cancer: in 27 of 82 pT1a tumours (32.9%) and in 100 of 320 pT1b tumours (31.25%). Patients and tumour characteristics were analysed to evaluate their influence on the decision to administer or not adjuvant chemotherapy (Table 4). Seventy-two out of 127 patients treated with chemotherapy were pN0 (56.69%). The multivariate logistic model analysis showed that younger age, grading G3, high proliferative index (≥ 30% Ki-67/Mib 1), ER negative status and HER2-positive status were significantly associated with the decision to administer adjuvant chemotherapy (Table 5).

Table 4 Adjuvant chemotherapy and patient/tumour characteristics
Table 5 Results of the multivariate logistic model analysis evaluating the probability of being treated with adjuvant chemotherapy for pT1a and pT1b breast cancers

The multivariate logistic analysis confirmed that ER negative status, high proliferation index, and HER2-positive status were significantly associated with the decision to administer adjuvant chemotherapy in patients with pT1b (Table 6), while it could not be performed for pT1a due to the low number of patients (=27). Both analyses excluded the evaluation of axillary lymph node status from the model fit because the distribution of population was unbalanced and it was impossible to estimate the values for the different categories.

Table 6 Results of the multivariate logistic model analysis evaluating the probability of being treated with adjuvant chemotherapy for pT1b breast cancers

We analysed the types of adjuvant chemotherapy administered in 127 patients with pT1a-pT1b tumours. Anthracycline without taxane regimen was administered in 59.1% of patients, anthracycline with taxane in 24.4%, CMF-like in 14.2% and taxane without anthracycline in only 2.4% (Table 7).

Table 7 Type of chemotherapy administered in 127 patients with pT1a, pT1b breast cancers

The small number of patients in the groups treated with different adjuvant chemotherapy regimens did not allow for a statistical evaluation of the patient and tumour characteristics which could have influenced the choice of adjuvant chemotherapy type.

In the few older patients (≥ 70 years) treated with chemotherapy, a CMF-like regimen was administered in 50%; in none of these patients was anthracycline and taxane-based adjuvant therapy chosen. A CMF-like regimen was chosen more frequently in postmenopausal patients (18.1% vs 9.6%), in patients with grade G1 tumours (22.2% vs 12.2% G3) and in patients with cancers having low or moderate proliferative indexes (14.5% and 25% respectively, versus 4.9% high proliferative index). In pT1b tumours, anthracycline and taxane-based regimen was chosen more frequently than in pT1a breast cancers (28% in pT1b vs 11.1% in pT1a) (Table 7).

Regarding compliance to adjuvant chemotherapy, it was observed that 105 of 127 patients (82.67%) received 4–6 cycles. Delays (> 7 days versus planned), were reported in 20 patients (15.7%), with a median delay of 7 days (range 7–28). The definitive interruption of chemotherapy occurred in only eight patients: three due to toxicity or severe adverse event, four due to the patient’s decision and one due to the investigator’s decision.

Hormonal therapy, planned in 351 of the 354 patients with hormonal receptor-positive tumours, was administered in 346 patients (97.7%). In pT1a-pT1b breast cancers, tamoxifen with or without LHRH was the hormonal therapy more frequently administered (85.3%) in premenopausal patients; aromatase inhibitors for 5 years (67.3%) was the endocrine treatment more often utilised in the postmenopausal setting, where tamoxifen for 2–3 years followed by aromatase inhibitor for 3–2 years was administered in 17.1% of patients (Table 8).

Table 8 Type of hormonal therapy administered according to menopausal status in 346 pT1a and pT1b tumours

Adjuvant chemotherapy in triple-negative pT1a and pT1b tumours

Triple-negative (ER = 0%, PgR = 0%, HER2-negative) pT1a-pT1 b tumours were 26 (6.5%); 2 were pT1a and 24 were pT1b. Adjuvant chemotherapy was administered in 88.4% of patients (23/26): in 1 of 2 patients with pT1a (50%) and in 22 of 24 pT1b patients (91.66%). A CMF-like regimen was administered in 6 patients (26.1%), anthracycline without taxane in 11 (47.8%), anthracycline with taxane in 5 (21.7%) and taxane without anthracycline in 1 (4.3%).

Adjuvant chemotherapy and adjuvant trastuzumab in pT1a and pT1b HER2-positive breast cancers

Forty-nine pT1a-pT1b tumours were HER2-positive (12.1%). Adjuvant chemotherapy was delivered to 36 of these 49 patients (73.46%): in 13/19 pT1a (68.4%) and in 23/130 pT1b (76.6%). Patient and tumour characteristics are reported in Table 9. Adjuvant chemotherapy was administered in 100% (19/19) of the younger patients (18–49 years) and in 100% (6/6) of patients with metastatic lymph nodes, in 90% (18/20) of tumours with negative hormonal receptors, and 69.6% and 84.2% of G2 and G3 tumours, respectively.

Table 9 Adjuvant chemotherapy and adjuvant trastuzumab by tumour and patient characteristics in HER2-positive pT1a and pT1b breast cancers (n = 49)

We observed that 30 out of 36 patients treated with adjuvant chemotherapy 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. An anthracycline-based regimen was administered in 34 of 36 HER2-positive patients (94.4%) (anthracycline without taxane in 72.2% and anthracycline with taxane in 22.2%); a CMF-like regimen in 1 patient (2.7%) and taxane without anthracycline in 1 patient (2.7%). In 30 out of 36 patients treated with chemotherapy, also adjuvant trastuzumab was administered. Trastuzumab was delivered in all six patients with lymph node involvement and in 24 patients with pN0 disease (Table 9).

Discussion

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, 2128], 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 [29]. 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 [30]. The 2007 St Gallen Consensus Conference [31] 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 [32] as well as in the NEMESI subgroup of triple-negative tumours [33].

Our study has some limits. Although the majority of pT1a-pT1b breast cancers had favourable prognostic factors, as reported in other retrospective studies [711], 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 [2224], as well confirmed by recent studies [2528]. 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%) [3438], 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 [41]. 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 [42]. 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 [43]. 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 [31], 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 [44].

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 [45].

Conclusions

In conclusion, the choice to deliver adjuvant chemotherapy to patients with pT1a-pT1b breast cancer treated at 63 Italian oncological centres from January 2008 to June 2008 was based on tumour biology. When it was decided to administer adjuvant chemotherapy, the most active regimens, anthracycline-based, were selected. Compliance to treatment was excellent.

References

  1. Grande E, Inghelmann R, Francisci S, Verdecchia A, Micheli A, Baili P, Capocaccia R, De Angelis R: Regional estimates of breast cancer burden in Italy. Tumori. 2007, 93 (4): 374-379.

    PubMed  Google Scholar 

  2. Botha JL, Bray F, Sankila R, Parkin DM: Breast cancer incidence and mortality trends in 16 European countries. Eur J Cancer. 2003, 39 (12): 1718-1729. 10.1016/S0959-8049(03)00118-7.

    Article  CAS  PubMed  Google Scholar 

  3. Glass AG, Lacey JV, Carreon JD, Hoover RN: Breast cancer incidence, 1980–2006: combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J Natl Cancer Inst. 2007, 99: 1152-1161. 10.1093/jnci/djm059.

    Article  PubMed  Google Scholar 

  4. Ferlay J, Parkin DM, Steliarova-Foucher E: Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010, 46: 765-781. 10.1016/j.ejca.2009.12.014.

    Article  CAS  PubMed  Google Scholar 

  5. Vacek PM, Geller BM, Weaver DL, Foster RS: Increased mammography use and its impact on earlier breast cancer detection in Vermont, 1975–1999. Cancer. 2002, 94: 2160-2168. 10.1002/cncr.10459.

    Article  PubMed  Google Scholar 

  6. Fracheboud J, Otto SJ, van Dijck JA, Broeders MJ, Verbeek AL, De Koning HJ, National Evaluation Team for Breast cancer screening (NETB): Decreased rates of advanced breast cancer due to mammography screening in The Netherlands. Br J Cancer. 2004, 91: 861-867.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Rosen PP, Groshen S, Kinne DW, Norton L: Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up. J Clin Oncol. 1993, 11: 2090-2100.

    CAS  PubMed  Google Scholar 

  8. Leitner SP, Swern AS, Weinberger D, Duncan LJ, Hutter RV: Predictors of recurrence for patients with small (one centimeter or less) localized breast cancer (T1a, b N0, M0). Cancer. 1995, 76: 2266-2274. 10.1002/1097-0142(19951201)76:11<2266::AID-CNCR2820761114>3.0.CO;2-T.

    Article  CAS  PubMed  Google Scholar 

  9. Arnesson LG, Smeds S, Fagerberg G: Recurrence-free survival in patients with small breast cancer. An analysis of cancers 10 mm or less detected clinically and by screening. Eur J Surg. 1994, 160: 271-276.

    CAS  PubMed  Google Scholar 

  10. Lee AK, Loda M, Mackarem G, Bosari S, DeLellis RA, Heatley GJ, Hughes K: Lymph node negative invasive breast carcinoma 1 centimeter or less in size (T1a, b N0 M0): clinicopathologic features and outcome. Cancer. 1997, 79: 761-771. 10.1002/(SICI)1097-0142(19970215)79:4<761::AID-CNCR13>3.0.CO;2-Y.

    Article  CAS  PubMed  Google Scholar 

  11. Tinnemans JG, Wobbes T, Holland R, Hendriks JH, Van der Sluis RF, De Boer HH: Treatment and survival of female patients with nonpalpable breast carcinoma. Ann Surg. 1989, 209: 249-253. 10.1097/00000658-198902000-00018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Crowe JP, Gordon NH, Shenk RR, Zollinger RM, Brumberg DJ, Shuck JM: Primary tumour size. Relevance to breast cancer survival. Arch Surg. 1992, 127: 910-915. 10.1001/archsurg.1992.01420080044007.

    Article  PubMed  Google Scholar 

  13. Moon TE, Jones SE, Bonadonna G, Valagussa P, Powles T, Buzdar A, Montague E: Development and use of a natural history data base of breast cancer studies. Am J Clin Oncol. 1987, 10: 396-403. 10.1097/00000421-198710000-00006.

    Article  CAS  PubMed  Google Scholar 

  14. Chia SK, Speers CH, Bryce CJ, Hayes MM, Olivotto IA: Ten-year outcomes in a population-based cohort of node-negative, lymphatic, and vascular invasion-negative early breast cancers without adjuvant systemic therapies. J Clin Oncol. 2004, 22: 1630-1637. 10.1200/JCO.2004.09.070.

    Article  PubMed  Google Scholar 

  15. Quiet CA, Ferguson DJ, Weichselbaum RR, Hellman S: Natural history of node-negative breast cancer: a study of 826 patients with long-term follow-up. J Clin Oncol. 1995, 13: 1144-1151.

    CAS  PubMed  Google Scholar 

  16. Fisher B, Dignam J, Tan-Chiu E, Anderson S, Fisher ER, Wittliff JL, Wolmark N: Prognosis and treatment of patients with breast tumors of one centimetre or less and negative axillary lymph nodes. J Natl Cancer Inst. 2001, 93: 112-120. 10.1093/jnci/93.2.112.

    Article  CAS  PubMed  Google Scholar 

  17. Associazione Italiana di Oncologia Medica (AIOM): Libro bianco. 2006, Italy, 3

    Google Scholar 

  18. Singletary SE, Allred C, Ashley P, Bassett LW, Berry D, Bland KI, Borgen PI, Clark G, Edge SB, Hayes DF, Hughes LL, Hutter RV, Morrow M, Page DL, Recht A, Theriault RL, Thor A, Weaver DL, Wieand HS, Greene FL: Revision of the American joint committee on cancer staging system for breast cancer. J Clin Oncol. 2002, 20: 3628-3636. 10.1200/JCO.2002.02.026.

    Article  PubMed  Google Scholar 

  19. Agenzia Italiana del Farmaco (AIFA): Linee guida per la classificazione e la conduzione di studi osservazionali su farmaci. 2008, Gazzetta Ufficiale. Serie ufficiale 76, Italy

    Google Scholar 

  20. World Medical Organization: Declaration of Helsinki (1964). BMJ. 1996, 313: 1448a-1449a.

    Google Scholar 

  21. Colleoni M, Rotmensz N, Peruzzotti G, Maisonneuve P, Viale G, Renne G, Casadio C, Veronesi P, Intra M, Torrisi R, Goldhirsch A: Minimal and small size invasive breast cancer with no axillary lymph node involvement: the need for tailored adjuvant therapies. Ann Oncol. 2004, 15: 1633-1639. 10.1093/annonc/mdh434.

    Article  CAS  PubMed  Google Scholar 

  22. Joensuu H, Isola J, Lundin M, Salminen T, Holli K, Kataja V, Pylkkänen L, Turpeenniemi-Hujanen T, von Smitten K, Lundin J: Amplification of erbB2 and erbB2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pT1N0M0 breast cancer: a nationwide population based study. Clin Cancer Res. 2003, 9: 923-930.

    CAS  PubMed  Google Scholar 

  23. Black D, Younger J, Martei Y, et al: Recurrence risk in T1a.-b, node-negative, HER positive breast cancer. Breast Cancer Res Treat. 2006, 100 (suppl 1): abstract 2037-

    Google Scholar 

  24. Chia S, Norris B, Speers C, Cheang M, Gilks B, Gown AM, Huntsman D, Olivotto IA, Nielsen TO, Gelmon K: Human epidermal growth factor receptor 2 overexpression as a prognostic factor and a large tissue microarray series of node-negative breast cancers. J Clin Oncol. 2008, 26: 5697-5704. 10.1200/JCO.2007.15.8659.

    Article  CAS  PubMed  Google Scholar 

  25. Gonzalez-Angulo AM, Litton JK, Broglio KR, Meric-Bernstam F, Rakkhit R, Cardoso F, Peintinger F, Hanrahan EO, Sahin A, Guray M, Larsimont D, Feoli F, Stranzl H, Buchholz TA, Valero V, Theriault R, Piccart-Gebhart M, Ravdin PM, Berry DA, Hortobagyi GN: High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol. 2009, 27: 5700-5706. 10.1200/JCO.2009.23.2025.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Curigliano G, Viale G, Bagnardi V, Fumagalli L, Locatelli M, Rotmensz N, Ghisini R, Colleoni M, Munzone E, Veronesi P, Zurrida S, Nolè F, Goldhirsch A: Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer. J Clin Oncol. 2009, 27: 5693-5699. 10.1200/JCO.2009.22.0962.

    Article  PubMed  Google Scholar 

  27. Tovey SM, Brown S, Doughty JC, Mallon EA, Cooke TG, Edwards J: Poor survival outcomes in HER2-positive breast cancer patients with low-grade, node-negative tumours. Br J Cancer. 2009, 100: 680-683. 10.1038/sj.bjc.6604940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Amar S, McCullough AE, Tan W, Geiger XJ, Boughey JC, McNeil RB, Coppola KE, McLaughlin SA, Palmieri FM, Perez EA: Prognosis and outcome of small (<=1 cm), node-negative breast cancer on the basis of hormonal and HER-2 status. Oncologist. 2010, 15: 1043-1049. 10.1634/theoncologist.2010-0036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Goldhirsch A, Glick JH, Gelber RD, Senn HJ: Meeting highlights: international consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst. 1998, 90: 1601-1608. 10.1093/jnci/90.21.1601.

    Article  CAS  PubMed  Google Scholar 

  30. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ: Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol. 2005, 16: 1569-1583. 10.1093/annonc/mdi326.

    Article  CAS  PubMed  Google Scholar 

  31. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ: Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer. Ann Oncol. 2007, 2007: 181133-181144.

    Google Scholar 

  32. Mustacchi G, Cazzaniga ME, Pronzato P, et al: Adjuvant chemotherapy for early breast cancer in Italy: what has changed today versus the early 2000’s. A comparison between two observational national studies. NORA and NEMESI. Ann Oncol. 2010, 21 (suppl 8): abstract 233P-

    Google Scholar 

  33. Adamo V, Ricciardi GRR, De Placido S, Colucci G, Conte P, Giuffrida D, Gebbia N, Masci G, Cognetti F, Dondi D, Venturini M: Management and treatment of triple-negative breast cancer patients from NEMESI study: an Italian experience. Eur J Oncol. 2011,  :  -

  34. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD, Herceptin Adjuvant (HERA) Trial Study Team: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005, 353: 1659-1672. 10.1056/NEJMoa052306.

    Article  CAS  PubMed  Google Scholar 

  35. Slamon D, Eiermann W, Robert N, et al: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2/neu positive early breast cancer patients. Breast Cancer Res Treat. 2006, 100: abstract 52-

    Google Scholar 

  36. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N: Trastuzumab with adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005, 353: 1673-1684. 10.1056/NEJMoa052122.

    Article  CAS  PubMed  Google Scholar 

  37. Spielmann M, Roché H, Delozier T, Canon JL, Romieu G, Bourgeois H, Extra JM, Serin D, Kerbrat P, Machiels JP, Lortholary A, Orfeuvre H, Campone M, Hardy-Bessard AC, Coudert B, Maerevoet M, Piot G, Kramar A, Martin AL, Penault-Llorca F: Trastuzumab for patients with axillary node positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol. 2009, 27: 6129-6134. 10.1200/JCO.2009.23.0946.

    Article  CAS  PubMed  Google Scholar 

  38. Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL: Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009, 27: 5685-5692. 10.1200/JCO.2008.21.4577.

    Article  CAS  PubMed  Google Scholar 

  39. Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sánchez Rovira P, Piccart-Gebhart MJ, HERA study team: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007, 369: 29-36. 10.1016/S0140-6736(07)60028-2.

    Article  CAS  PubMed  Google Scholar 

  40. Untch M, Gelber RD, Jackisch C, Procter M, Baselga J, Bell R, Cameron D, Bari M, Smith I, Leyland-Jones B, de Azambuja E, Wermuth P, Khasanov R, Feng-Yi F, Constantin C, Mayordomo JI, Su CH, Yu SY, Lluch A, Senkus-Konefka E, Price C, Haslbauer F, Suarez Sahui T, Srimuninnimit V, Colleoni M, Coates AS, Piccart-Gebhart MJ, Goldhirsch A, HERA Study Team: Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol. 2008, 19: 1090-1096. 10.1093/annonc/mdn005.

    Article  CAS  PubMed  Google Scholar 

  41. Rodrigues MJ, Wassermann J, Albiges L, Brain E, Delaloge S, Stevens D, Guinebretière JM, Mathieu MC, Kirova Y, Guillot E, Vincent-Salomon A, Cottu PH: Trastuzumab treatment in T1ab, node-negative, human epidermal growth factor receptor 2-overexpressing breast carcinomas. J Clin Oncol. 2010, 28: e541-e542. 10.1200/JCO.2010.29.7952.

    Article  PubMed  Google Scholar 

  42. McArthur HL, Mahoney K, Morris PG, Patil S, Jacks LM, Howard J, Norton L, Hudis C: Use of adjuvant trastuzumab with chemotherapy in women with small, node-negative, HER2-positive breast cancers. J Clin Oncol. 2010, 28 (7s): abstr 615-

    Google Scholar 

  43. Chew HK, Brown M: Cause-specific and all-cause mortality of HER2-positive, node-negative, T1a and T1b breast cancers. J Clin Oncol. 2010, 28 (7s): abstr 583-

    Google Scholar 

  44. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn H-J, Panel members: Strategy for subtypes- dealing with the diversity of breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2011. Ann Oncol. 2011, 22: 1736-1747. 10.1093/annonc/mdr304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Roila F, Ballatori E, Patoia L, Palazzo S, Veronesi A, Frassoldati A, Cetto G, Cinieri S, Goldhirsch A: Adjuvant systemic therapies in women with breast cancer: an audit of clinical practice in Italy. Ann Oncol. 2003, 14: 843-848. 10.1093/annonc/mdg256.

    Article  CAS  PubMed  Google Scholar 

Pre-publication history

Download references

Acknowledgements

The NEMESI study was funded by Sanofi-Aventis. The sponsor did not interfere in any way in the interpretation of data or in the content of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stefania Gori.

Additional information

Competing interests

The authors declare that they have no competing interests except for D. Dondi who is an employee of Sanofi-Aventis.

Authors’ contribution

All authors have contributed to the conception and design of the study, acquisition and interpretation of data. Stefania Gori was responsible for drafting the manuscript. All authors have given approval to this version of the manuscript.

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Gori, S., Clavarezza, M., Siena, S. et al. Adjuvant chemotherapy of pT1a and pT1b breast carcinoma: results from the NEMESI study. BMC Cancer 12, 158 (2012). https://doi.org/10.1186/1471-2407-12-158

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1471-2407-12-158

Keywords