Breast cancer is the most common cancer and the leading cause of death among women in Italy and worldwide.1 The time trends of breast cancer incidence have increased in most European countries, including Italy, starting from the end of the 1990s. Conversely, widespread reductions in mortality rates have been observed in Europe, including Italy, starting in the early 1990s.2, 3
The increased incidence of breast cancer may be explained in part by the implementation of organized screening programs (SMPs). Conversely, the widespread reduction in mortality rates probably is attributable to advancements in medical treatments and to the role of mammography screening in detecting cancers at an earlier stage.4-8
MATERIALS AND METHODS
In Italy, a well organized network of population-based cancer registries, the Association of Italian Cancer Registries, collects data on new cancer diagnoses and on cancer deaths to provide reliable data on cancer incidence, mortality, survival, and (more recently) cancer time trends.9, 10 The number of active population-based cancer registries in Italy has increased overtime; and, today, there are 21 active cancer registries in the country. The geographic distribution of the registries is not homogeneous across Italy. In fact, most data are acquired in the northern and central regions of Italy, whereas scant data are available for populations in the southern regions of Italy.
Overall, the population that is covered by general cancer registries includes approximately 15 million inhabitants, which represents 25.5% of the entire Italian resident population. In more detail, the population that is covered by registries is 36.8% in the northern regions, 25.5% in the central regions, and 11.5% in the southern regions.11
The increased incidence of breast cancer is related mainly to the implementation of SMPs for women ages 50 to 69 years, especially in the northern-central regions of Italy. An increased rate in the diagnosis of early stage breast cancer also has been observed among all age groups. Conversely, a decrease in mortality from breast cancer has been reported. These findings may be explained at least in part by the spread of SMPs, which have led to an increased rate of diagnosis of early stage breast cancers with a better prognosis. Improvements in breast cancer care (eg, faster diagnosis, multidisciplinary approach, novel treatments, etc) also have contributed to better outcomes.4
Currently, there are 121 active SMPs in Italy, and they are restricted mostly to the northern regions of the country. In the southern regions, only a few areas are covered by SMPs; and, within these SMPs, it is well documented that there has been poor participation of the target population. In more detail, the population covered by SMPs is >80% in northern regions but <40% in the southern regions of Italy.12-14
The heterogeneous distribution of SMPs across Italy may help explain the different trends over time in incidence and mortality between northern and southern regions. Specifically, the southern regions have observed a higher mortality, which has been attributed at least in part to delayed diagnosis. Conversely, the southern regions have observed a lower incidence, which is related in part to the lower diffusion of SMPs.4, 11
Moreover, it is well recognized that several prognostic variables may influence cancer survival rates in Italy, such as demographic and socioeconomic conditions or the total expenditure on health (high-cost technologies and new anticancer drugs). These variables also are applicable to breast cancer, and there is a consistent gradient in terms of survival from northern regions to southern regions of Italy where worse outcomes are observed.15-17
Epidemiology of IBC and T4 Non-IBC in Italy
Stage IIIB breast cancer includes both noninflammatory T4a, T4b, and T4c disease and inflammatory T4d disease. In Italy, the common American Joint Committee on Cancer definition is used to identify IBC: inflammatory carcinoma is defined as a clinical-pathologic entity characterized by diffuse erythema and edema (peau d'orange) of the breast, often without and underlying mass. These clinical findings should involve the majority of the breast. Dermal lymphatic involvement may or not be present on skin biopsy.18
To date, only a few Italian cancer registries have reported data on breast cancer incidence according to the stage at diagnosis.19-22 Therefore, few data are available from the cancer registries concerning the incidence of IBC over time in Italy. The major difficulties are related to the possibility of collecting data on IBC properly because of its unclear definition. In addition, inflammatory T4d breast cancers and T4a, T4b, and T4c breast cancers often are grouped together as undefined T4 disease.
On the basis of the available data, we have attempted to retrospectively analyze the incidence over time for the whole T4 group, including both IBC and non-IBC, compared with T1, T2, and T3 breast cancers among 2 population groups in Italy. The first group was identified by acquiring data from the different cancer registries in which SMPs are active across Italy. The second group was identified by acquiring data from patients who were not included in active SMPs of the biggest cancer center located in Sardinia (southern Italy).
The distribution by stage at diagnosis over time in the population that was covered by SMPs revealed a clear decrease in the incidence of T4 disease compared with earlier stage disease from 9.4% in the 1990s to 6.8% in the 2000s (Fig. 1a). Conversely, the distribution in the population that was not covered by SMPs indicated a stable incidence of T4 disease compared with earlier stage disease (approximately 9%) (Fig. 1b).
Regarding IBC, we observed a decrease in incidence overtime in the group that was covered by SMPs. In particular, when considering all T4 cancers, the proportion of IBC versus T4a, T4b, and T4c breast cancer changed from 11% and 89%, respectively, in the 1990s to 6% and 94%, respectively, in the 2000s (Fig. 2a). Conversely, in the areas that are not covered by SMPs, we have observed a slight increase in the incidence of IBC: The proportion of IBC versus T4a, T4b, and T4c breast cancer increased from 23% and 77%, respectively, in the 1990s to 25% and 75%, respectively, in the 2000s (Fig. 2b).
On the basis of the estimated 40,000 new cases of breast cancer in Italy per year, we attempted to extrapolate the approximate incidence of new cases of T4 breast cancer, which should be between 2800 and 3600 new cases per year, taking into account the different gradient of incidence observed in areas covered or not covered by SMPs. Following the same extrapolations, the approximate incidence of IBC should be approximately 200 to 800 new cases per year, representing 0.6% to 2% of all breast cancers diagnosed every year in Italy.
IBC and T4 Non-IBC in Italy: A Single-Institution Experience
Between 1990 and 2007 in the Department of Medical Oncology at the University of Cagliari (Italy), an observational retrospective study was conducted. There were 336 patients with T4 breast cancer in the study, including 265 patients with T4a, T4b, and T4c disease and 71 patients with T4d disease.
All patients received an identical multidisciplinary treatment approach with primary chemotherapy, surgery, radiation therapy, and hormone therapy, if indicated. Between 1990 and 1996, the patients received older standard primary chemotherapy regimens (eg, 5-fluorouracil, epirubicin, and cyclophosphamide; epirubicin and cyclophosphamide; or cyclophosphamide, methotrexate, and 5-fluorouracil). From 1996 onward, patients received new standard regimens, including intensified cisplatin-epirubicin with or without taxanes.23
RESULTS AND DISCUSSION
The main objective of this study was to identify and characterize the differences between patients with T4a, T4b, and T4c breast cancer and patients with T4d breast cancer (IBC) in terms of age at diagnosis, clinical and pathologic tumor features, and outcomes. Survival was estimated by using the Kaplan-Meier method, and differences between groups were tested with the log-rank test.
Among all patients with T4 breast cancer, the distribution according to age at diagnosis of IBC revealed a peak of incidence (32%) in younger patients (ages 0-44 years) compared with an incidence of 27% for non-IBC in the same age group (Fig. 3a). With regard to biologic and clinical-pathologic characteristics according to disease stage (IBC vs T4 non-IBC) the percentage of estrogen receptor (ER)-negative tumors in IBC was 61% versus 34%; the percentage of progesterone receptor (PgR)-negative tumors was 72% versus 48%, respectively; the percentage of human epidermal growth factor receptor 2 (HER-2)-positive tumors was 33% versus 24%, respectively; and the percentage of triple-negative (ER-negative, PgR-negative, and HER-2–negative) tumors was 33% versus 15%, respectively. In terms of response rates, 15% of patients with IBC obtained pathologic complete remission (pCR) after primary chemotherapy versus 14% of patients with non-IBC, and 25% of patients with IBC had extensive residual disease in the axilla versus 14% of patients with T4 non-IBC (Fig. 3b).
After a median follow-up of 101 months (range, 8-217 months), the 10-year disease-free survival (DFS) rate was 37.2% in patients with IBC and 47.1% in patients with T4 non-IBC (P = .106), and the overall survival (OS) rate was 41.9% in patients with IBC and 61.5% in patients with T4 non-IBC (P = .03).
The median time to recurrence for patients with IBC (16 months; range, 5-62 months) was shorter than that for patients with T4 non-IBC (20 months; range, 3-122 months). It is noteworthy that, during the first 2 years of follow-up, the percentage of total recurrences was 79% in patients with IBC compared with 56% in patients with T4 non-IBC. The 10-year DFS rate according to pathologic response to primary chemotherapy in patients who achieved pCR was 75% in patients with IBC versus 80% in patients with T4 non-IBC (P = .814), and 33.3% of patients with IBC and 41.6% of patients with T4 non-IBC achieved less than pCR (P = .146). The OS rate for patients who achieved a pCR was 100% in patients with IBC and 86.7% in patients T4 non-IBC (P = .455), and 35.9% of patients with IBC versus 57.3% of patients with T4 non-IBC achieved less than pCR (P = .029). The 10-year DFS rate for patients with IBC according to the type of regimen administered was 9.5% with the old standard regimens and 63.6% with the new standard regimens (P = .004). The OS rate was 14.3% in patients who received old standard regimens versus 68.2% (P = .005) in patients who received new standard regimens.
The distribution according to age at diagnosis revealed a higher incidence of IBC among younger patients (aged <44 years). With regards to biologic and clinicopathologic characteristics, patients with IBC were more likely to be ER-negative, PgR-negative, triple-negative, and HER-positive. Although no differences were observed in terms of pCR rates after primary chemotherapy, patients with IBC had a higher rate of extensive residual disease in the axilla. Although patients with IBC have a worse prognosis than patients with non-IBC, the outcomes were similar for patients who achieved pCR regardless of their disease stage.
Overall, patients who had IBC had worse DFS and OS compared patients who had non-IBC irrespective of the treatment received. However, the outcomes were statistically better for patients with IBC who received new standard regimens, including cisplatin and taxanes, compared with old regimens, which included anthracyclines or cyclophosphamide, methotrexate, and 5-fluorouracil-like regimens. The clinical and pathologic findings are consistent with data from the United States and reinforce the idea that IBC is a distinct biologic entity compared with noninflammatory, locally advanced breast cancer.24-29
In January 2008, the Italian Registry Stage T4 Breast Cancer (RITMA4) project was launched. RITMA4 is a national, multicenter observational study that is being conducted in >100 active centers to date, and its main objective is to evaluate the incidence, clinical and pathologic features, and outcomes of patients with T4a, T4b, T4c, and T4d breast cancer in Italy. Data that will be collected include risk factors (eg, age at diagnosis, age at first birth, etc), demographic and socioeconomic characteristics, therapeutic approaches (eg, type of chemotherapy, targeted therapies, surgery, etc), and natural history of the disease (eg, survival, site of recurrence, etc).
The project RITMA4 is scheduled to last for approximately 3 years. Afterward, we should be able to furnish more exhaustive data regarding the epidemiological and clinical aspects of T4a, T4b, T4c, and T4d breast cancer in Italy.
In conclusion, IBC in Italy represents a rare but very aggressive type of breast cancer. Because of the nonhomogeneous distribution of cancer registries across Italy, it is difficult to define the exact epidemiology of T4 breast cancer, including IBC, in Italy. Although the available sources were scarce, we attempted to extrapolate data on the incidence of IBC that were more likely to correspond to the existing situation in Italy. We observed a lower incidence of IBC in Italy in the regions that were covered by SMPs. It is noteworthy that the clinical and biologic characteristics of IBC in Italy were quite similar to those of IBC in the United States and that the disease had the same behavior. The RITMA4 study may contribute toward improving our understanding of IBC.
CONFLICT OF INTEREST DISCLOSURES
This supplement was sponsored by the Houston Affiliate of the Susan G. Komen for the Cure, the National Cancer Institute, and the State of Texas Rare and Aggressive Breast Cancer Research Program. The First International Inflammatory Breast Cancer Conference was supported in part by GlaxoSmithKline, Pfizer, Eli Lilly and Company, and Cardinal Health.