Tumour characteristics and survivorship in a cohort of breast cancer: the MCC-Spain study

The breast cancer MCC-Spain follow-up study is a prospective cohort study of incident breast cancer cases diagnosed between 2008 and 2013 in 18 hospitals located in 10 Spanish provinces (Asturias, Barcelona, Cantabria, Girona, Gipuzkoa, Huelva, León, Madrid, Navarra and Valencia). 1738 women between 20 and 85 years old with newly diagnosed primary breast cancer were recruited in the context of a case–control study. The identification of incident cases was carried out by active search through periodic visits to the relevant hospital departments (i.e. gynaecology, oncology, general surgery, radiotherapy and pathology departments). All the cases that were included had histological confirmation and included all the malignant BC (International Classification of Diseases 10th Revision (ICD-10) [15] code C50) and frequent breast cancers in situ (ICD-10: D05.1, D05.7), without a malignant history of BC, diagnosed between 2008 and 2013 in the selected hospitals. Patients were residing in the catchment areas of hospitals for at least 6 months before recruitment. A detailed description of methods and sample characteristics has been published elsewhere [16, 17] and then, 98% recruited patients have been followed until 2017/2018 (N = 1685). Only patients signing an informed consent were recruited; the informed consent also asked them for their permission for later consulting their medical records during the follow-up.

When the patients were recruited, medical records were reviewed in order to gather information on age, date of diagnosis, tumour characteristics, including tumour size, lymph nodes, presence of metastases, grade of differentiation. Furthermore, oestrogen (ER), progesterone (PgR) and human epidermal growth factor receptor 2 (HER2) status were assessed and then classified as positive (+), negative (−) and unknown. Specifically, ER and PgR were considered positive if 1% or more of neoplastic cells showed nuclear immunohistochemical (IHC) staining. HER2 was considered positive (overexpressed) if graded 3 + on IHC performed, and all other grades (0 to 2 +) were considered negative unless fluorescence in situ hybridization of 2 + cases confirmed increased gene copy number. Molecular subtypes of breast carcinoma is classified into luminal A (ER + and / or PR + , HER2-, Ki-67 < 14%), luminal B (ER + and / or PR + , HER2-, or ER + and / or PR + , HER2-, Ki-67 ≥ 14%), HER2 + (ER-, PR-, HER2 +) and basal-like or triple negative is a tumour which does not meet any pathologic criteria for positivity of oestrogen receptor, progesterone receptor, or ERBB2 (ER-, PR- and HER2-) [6]. Tumour stage was based on the AJCC standards [18]. Tumour size was classified as T1: ≤ 2 cm, T2: > 2 cm and ≤ 5 cm, T3: > 5 cm, T4: any size with direct extension to chest wall and/or skin; lymph node involvement was classified as N0: no pathologically proven positive lymph nodes, N1: 1–3 positive nodes, N2: 4–9 positive nodes, N3: ≥ 10 positive nodes. Tumour grade was categorised as I: well differentiated, II: moderately differentiated, III: poorly differentiated, according to the modified Bloom and Richardson grading system [19]; when Bloom and Richardson grade was unavailable, other similar classifications were used as it has been proved they are highly reliable [20]. First-line therapy was also recorded, including type of surgery (conservative or mastectomy), margins (free or invaded), chemotherapy regime, radiotherapy, endocrine therapy, Her2-targeted therapy; for all systemic therapies, whether they were adjuvant or neoadjuvant was also recorded.

In 2017 and 2018, medical records were reviewed to obtain the last date the patient was attended to in t the health system and to ascertain current patient’s vital status. For patients that had not have been at hospital in the 3 months before their medical record review, the National Death Index (Índice Nacional de Defunciones) was consulted [21]. This index is a database recording date of death for all people who have died in Spain; it is hosted on the Ministry of Health web page and can only be accessed with specific authorisation for research purposes. Last date of search in the National Death Index was in December 2018.

Deaths by any cause were considered events and patients alive in their last contact with hospital and not included in the National Death Index were considered censored. Time of follow-up was considered as the time from diagnosis to death or to the last contact in hospital in alive patients. Relative survival, defined as the ratio of the observed survival in our study population and the expected survival in general population Spanish women with the same age as cases in the year of diagnosis, was estimated using Ederer II method [22]; for this purpose, age-specific mortality rates from 2007 to 2018 obtained from the Spanish National Institute for Statistics (INE) were used as reference. 3-, 5- and 8-year survival Kaplan–Meier estimates were obtained. Weibull regression adjusting by age, hospital, grade and stage was used to investigate prognosis factors; its results are displayed as hazard ratios with their 95% confidence intervals. Groups that included less than 25 people were excluded from this analysis. Stata 14/SE package was used in the analyses.

We followed 1685 women out of 1738 breast cancer patients (98%), who had primary breast cancer between 2007 and 2013. Patient-years of follow-up were 10,931 person-years. The maximum period for breast cancer follow-up was nine and a half years (from 13th July 2007 to 22nd March 2018) and 206 patients died in the follow-up; 5-year survival was 90.7%.

The mean age at diagnosis was 56.5 ± 12.6-year-old and 65% were postmenopausal. Other main characteristics of the patients are shown in supplementary Table 1.

Regarding the characteristics of the tumours, the most usual histological type was ductal (75.7%), followed by lobular (6.5%). About half of cancers were T1 (52%) and lymph node negatives (52%). Only 42 women (2.5%) had metastasis at the time of diagnosis.

Concerning intrinsic subtypes, 997 (59.2%) could be classified as luminal A-like, 331 (19.6%) as luminal B-like, 81 (4.8%) as Her2 (non-luminal)-like and 130 (7.7%) as basal-like. Grade of differentiation could not be obtained from medical records in 481 patients (28.5%). Almost 31% of the cancers were moderately differentiated while poorly differentiated accounted for about 21% cancers. Hormone receptor status was available for most cases; 83% were oestrogen receptor positive, 73% progesterone positive and 17.4% were Her2 positive (Table 1).

5-year relative survival with breast cancer was 93% (95% CI 92 – 94) (Fig. 1a). Table 1 shows 3-, 5- and 8-year relative survival according to tumour characteristics. Women diagnosed in stage I had the same survival probability than women with the same age without breast cancer (i.e. 100% relative survival) even after 8 years of follow-up. At the same time, relative survival decreased with follow-up time in women diagnosed in more advanced stages: 3-, 5- and 8-year relative survival were 98%, 95% and 93% for breast cancer diagnosed in stage II, 94%, 88% and 81% in women diagnosed in staged III and 63%, 40% and 24% in those diagnosed in staged IV (Table 1 and Fig. 1b). Relative survival also decreased as grading got less differentiated [8-year relative survival: 99% in well differentiated tumours, 93% in moderately differentiated and 88% in poorly differentiated (Table 1 and Fig. 1c)]. Relative survival after 8 years of follow-up was 94% for luminal A-like breast cancers, 88% for luminal B-like, 82% for Her2 non-luminal) and 74% for basal-like cancers (Table 1 and Fig. 1d).

Age, hospital, stage and grade-adjusted hazard ratios on association between survival and tumour characteristics and first-line treatment are displayed in Table 2. Age, premenopausal status, tumour size, nodal infiltration and presence of metastasis were significantly associated with overall mortality. Hazard ratios increased with tumour stage, being 1 (reference) for T1 and 1.62 (1.04 – 2.52) and 2.04 (1.13 – 3.68) for T2, T3, respectively. Breast cancers negative for oestrogen or progesterone receptors behaved worse than their opposite. Luminal A- like and luminal B-like tumours had similar prognosis; hazard for Her2 (non-luminal) cancers were 50% higher than for luminal A-like (hazard ratio = 1.50; 95% CI 0.87 – 2.59), and basal-like tumour’s hazard was three times that of luminal A-like (hazard ratio = 3.50; 95% CI 2.31 – 5.30). Grading showed a dose–response association with mortality, with hazard ratios 1 (reference) for well differentiated cancers, 1.48 (0.86 – 2.54) for moderately differentiated and 2.42 (1.41 – 4.17) for poorly differentiated. To further explore whether intrinsic subtype adds prognosis value to tumour stage, we studied the effect of stage by stratifying for intrinsic subtype; results in Fig. 2a show that higher stages had higher hazard ratios, whatever the intrinsic subtype. However, when stratifying the effect of intrinsic subtype for tumour stage, we found that intrinsic subtype had no effect at all in patients in stage I, while Her2 (non-luminal) and basal-like tumours had worse prognosis than luminal-like tumours in patients with stage II and, especially, stages III and IV (Fig. 2b).