The results of this observational study, conducted throughout oncologic centres of Northern, Central and Southern Italy, is representative of Italy with respect to the choice of adjuvant chemotherapy for breast cancer.
The first important consideration is about demography and biology of breast cancer of this population study. In fact, most patients (85.5%) had ER or PgR-positive (≥1%) breast cancer, while only 14.5% had both ER and PgR 0%. Triple negative cases were 8.7%, 16.1% HER2-positive independently from hormonal receptors status. These results are probably influenced by a high proportion of postmenopausal patients (nearly 70%) and by those aged ≥70
years (21.7% of the population study). In the previous reported observational study conducted by Cazzaniga et al. between 2000 and 2004 [17
], elderly patients were 18.5%, despite the biological characteristics being similar to this study.
The second important consideration is about stage. In the current study there is a lower incidence of high-risk nodal disease (pN2-pN3), which decreased from 17.1% of NORA to 9.9% of NEMESI study (p
0.0001). This is probably due to more extensive use of breast cancer screening in recent years in Italy. Probably, for the same reason, pT1 increased from 59.7% of patients in NORA to 67.0% of NEMESI (p
These demographical, pathological and biological characteristics seem to be in contrast with the high rate of adjuvant chemotherapy prescription. 57.8% of the population study received adjuvant chemotherapy. Population study was composed by 85% of endocrine responsive breast cancers, 84% of HER2 negative, 61% of node-negative and 2 of 3 cases with tumor diameter inferior to 2
cm, 22.3% ≤1
cm. International guidelines recommend the use of adjuvant chemotherapy on the basis of all prognostic and predictive parameters but in general it is not recommended for patients with pT1, pN0, ER-positive, low proliferation index, HER2 negative breast cancer. We noted that, overall, 38.1% of luminal A population was treated with adjuvant chemotherapy: 6% in stage IA, 22.6% in stage IB, 56.2% in stage II, 81.0% in stage III. It means that 33.8% of luminal A with low (pT1 pN0) or intermediate recurrence risk (pT2/pT3 pN0 or pN1) was treated with adjuvant chemotherapy. 25% of entire study population receiving adjuvant chemotherapy was luminal A with low or intermediate risk recurrence. This fact underlines an overtreatment and over prescription with adjuvant chemotherapy. In fact, luminal A is recognized as the less sensitive breast cancer subtype to adjuvant chemotherapy. The cut-off for luminal A was set to a proliferative index ≤20%. As indicated by Cheang et al., ki67 of 14% is considered the proliferation index able to distinguish luminal A versus luminal B [18
]. Modifying the cut-off value of proliferative index from 20% to 14% in order to distinguish between luminal A versus luminal B we obtained similar data: 29.5% of luminal A with stage IA, IB, II was treated with adjuvant chemotherapy and OR for the use of adjuvant chemotherapy in luminal B versus luminal A was 1.95 (OR
1.40-2.72) similar to that reported in Table .
NEMESI study identified tumor and patient characteristics that were important determinants in the decision to prescribe a chemotherapy regimen and the choice of chemotherapy type. Whereas adjuvant chemotherapy prescription by Italian oncologists is influenced by prognostic and predictive parameters, type of adjuvant chemotherapy is significantly influenced by age, menopausal status and above all by the risk of recurrence (pT and pN), but not by biological predictive factors. In fact, prescription of CMF-like regimen decreases with increasing pT and pN in favor of the use of anthracyclines plus taxanes. In particular, as previously reported, considering small tumors pT1a and pT1b compared to larger tumors, CMF-like prescription decreases from 14.2% to 9.9% of pT1c and 6.9% of pT2, pT3, pT4b [19
]. More recurrence risk is, more is the use of the most effective regimen anthracyclines plus taxanes. The choice for anthracyclines plus taxanes should be considered not on the basis of pT and pN but on the basis of sensitiveness to chemotherapy. As indicated by St. Gallen guidelines, luminal B, HER2 and triple negative should receive both anthracyclines and taxanes, which, on the contrary, are treated with this regimen in only 37.0%, 43.5% and 36.6% of cases, respectively.
Another important issue is about older age and prescription of the type of adjuvant chemotherapy. In fact, administration of CMF-like regimen was more frequently used for women aged ≥70 (27.0%) than for women under 70 (9.1%) and, as previously reported, this percentage increased until 50% considering only pT1a and pT1b tumors [19
]. This choice is in contrast with data from randomized trials conducted in elderly women in whom CMF-like was demonstrated to be more toxic and less feasible compared to anthracyclines, like AC regimen [20
On multivariate analysis, the only biological parameter little influencing the choice of chemotherapy type is HER2. In HER2-positive breast cancer patients, anthracyclines use increased; this is probably also influenced by the results of a meta-analysis by Gennari et al. [21
]. There was an overall increase in anthracyclines use in HER2-positive versus HER2-negative patients (absolute increase: 9.4%); however, while anthracyclines alone were prescribed equally between HER2-positive and HER2-negative patients, there was higher use of anthracyclines plus taxanes in HER2-positive versus HER2-negative patients (absolute increase: 6.9%). This data is also consistent with a meta-analysis conducted by De Laurentiis et al. [22
] which demonstrated that chemotherapy containing anthracyclines plus taxanes is more effective than anthracyclines alone in HER2-positive breast cancer.
Finally, patients treated with chemotherapy included schedules with CMF-like regimen or AC/EC for four cycles. Recently, EBCTCG demonstrated that these regimens remain suboptimal schedules in terms of efficacy. We know from EBCTCG metanalysis that more effective chemotherapy regimens included anthracyclines with doxorubicin with a dose of at least 60
per cycle or epirubicin with a dose of at least 90
per cycle with cumulative dose of more than 240
, respectively, or regimens including anthracyclines plus taxanes [23
]. Overall, 25.3% of population study was treated with CMF-like or AC/EC four cycles and 12% with FEC for 6 cycles but with suboptimal epirubicin dose per cycle (75
). These data were confirmed also for particular sensitive disease to chemotherapy, HER2-positive and triple negative, in which suboptimal chemotherapy with CMF-like or AC/EC for 4 cycles was prescribed in 24.2% and 22.2%, respectively. FEC 6 cycles with epirubicin 75
was adopted in 12.3% and 11.8%, respectively.