In the present study, we analyzed data from a clinical series of 448 women with operable breast cancer and compared characteristics related to patients tumour, treatment, and outcomes by mode of breast cancer detection. We observed more favourable prognostic factors and survival outcomes in women with screen detected breast cancers compared with symptomatic patients. The independent role of mode of breast cancer detection was not confirmed in multivariate analyses including age, tumour size and nodal status. However, adjusted and unadjusted HR did not dramatically differ and the two 95% CIs largely overlapped.
Based on the hypothesis of a potential role of breast cancer biology in explaining the impact of mode of breast cancer detection on survival outcomes, we re- analyzed data within strata defined by molecular subtypes. Overall, screen detected cancers tended to show more favourable prognostic features across the various molecular categories. However, screen detected cancers showed significantly better disease free and overall survival compared to symptomatic tumours in the luminal A subtype only. In this subcategory, the multivariate analyses confirmed the independent role of mode of detection on recurrence, while there was only a suggestion for its role on death.
Breast cancers in the screen detected group tended to be smaller, more often node negative and with lower histological grade compared with tumours in the symptomatic group. Patients in this group tended to be older. Age at breast cancer diagnosis is an independent prognostic factor, with younger age associated to having more aggressive tumour behaviour
. Screen detected tumours were more likely to express ER and/or PgR and to show a lower Ki67 index. The more favourable clinicopathological characteristics provide a rationale for the more conservative surgical approach and less frequent administration of adjuvant therapy in screen detected tumours. These findings are consistent with the results of previous studies
In our study, screen detection was associated with better survival outcomes. The survival advantage conferred by screening has been mostly attributed to stage shift, i.e. the proportional shift toward earlier-stage cancer at presentation. The latter is a reflection of screening-related lead-time bias, which lengthens survival duration and explains, at least partly, the observed improvement in outcomes of patients with screen detected tumours
[19–22]. However, consistent evidence supports an independent prognostic role of screen detection after adjustment for disease stage. Indeed, Dawson and colleagues compared the effects of screen detection with symptomatic diagnosis on survival after adjustment for the Nottinghan Prognostic Index, a prognostic indicator based on tumour size, grade and lymph node status. The authors concluded that the shift in NPI accounted only for the fifty-six per cent of the survival benefit associated with screen detection
In our study, symptomatic breast cancer patients tended to be significantly younger. Younger age at breast cancer diagnosis is associated with more aggressive tumour behavior and might help interpret differences in outcomes by mode of detection
Based on pre-set inclusion criteria, inoperable breast cancer cases were excluded from our analysis. We cannot estimate their exact proportion and distribution across the study groups. However, given the tendency of screen detected tumours to show smaller size compared to symptomatic cases, we may presume that inoperable cancer were more represented among symptomatic patients, thus eventually contributing to worse survival outcomes in this subgroup.
Our results might help explain the role of tumour biology in affecting differences in survival outcomes between women diagnosed with screen detected tumours and symptomatic patients. Indeed, we observed a significantly higher percentage of luminal A subtype among women within the screen detected group compared to patients with symptomatic tumours. Conversely, the triple negative subtype was significantly more common among symptomatic patients compared to women with screen detected tumours. This is consistent with the results reported by Kim et al. and Dawson et
[23, 25]. Molecular subtypes are largely and consistently recognized as predictors of recurrence and death
[10–12]. Since the luminal A subtype is usually associated with more favorable outcomes, it is plausible that the significantly higher proportion of this molecular subtype within the screen detected group (compared with the symptomatic group) might explain at least in part the survival advantage observed in women with a screen detected cancer
When comparing tumour characteristics and outcomes of interests between screen detected and symptomatic cancers across categories defined on the basis of the molecular subtypes, the number of predictors of a more favorable prognosis was remarkable in the luminal A subtype only. This was the only subtype associated with a significant advantage in survival outcomes. These findings might strengthen the evidence in supporting a selective influence of early detection on survival in less aggres-sive tumours, i.e. luminal A subtype. Conversely, doubts remain concerning the efficacy in the amelioration of survival outcomes for more aggressive tumours.
A limited number of studies have investigated the association of interest so far. Kim and coauthors retrospectively reviewed the clinical and pathologic data from 3,141 patients who underwent surgery for the treatment of invasive breast cancer at the Samsung Medical Center. Consistently with our results, the authors observed more favorable prognostic survival outcomes in screened-detected breast cancers compared with symptomatic cases (5-year OS: 99.7 vs. 96.5%, p=0.001 and DFS: 96.4 vs. 90.7, p<0.001). Screen detection was independently associated with improved OS and DFS after adjustment for covariates (HR=0.32, p=0.0035; HR: 0.58, p=0.020, respectively)
. We have previously mentioned the analysis from Dawson et al., including data from 1379 women with invasive breast cancers. The authors identified distinct differences in the molecular characteristics of screen-detected vs. symptomatic breast cancers. However, only minimal attenuation of the screen-detected survival advantage was observed after adjustment for the expression of individual molecular biomarkers or molecular subtype in multivariate analysis. Indeed, the percentage of survival benefit attributable to these factors was 3-10%, with more than 30% of the effect remaining unexplained
. In a recent study by Shito and coauthors, screen detection was an independent predictor of favourable distant disease-free survival in multivariate analysis including age, grade and tumour size. According to the authors’ conclusions, differences in molecular subtypes of screen-detected vs. symptomatic breast cancers accounted in part for the better outcome of screen-detected cancers. However, the effect of molecular subtype on the survival advantage conferred by screen detection was not assessed in this analysis
Our study has some limitations. We analyzed data from a clinical series of 448 women with operable breast cancer. The sample size limitations mostly reflect on the non-Luminal A subgroups, which are particularly under-represented among patients included in our analysis. Our study might lack sufficient power to highlight the impact of molecular determinants on survival outcomes by detection mode in non-Luminal A patients. When assessing the interaction between mode of breast cancer and molecular subtypes for the outcomes of interest, we observed non significant results. However, interaction effects are often undetectable in subgroup analyses when sufficient power is lacking
. The relatively limited sample size and study design, i.e., clinical series, both concur to limit the ability to make definitive interpretation of this data and encourage conducting further research based on specifically conceived, adequately powered, prospective studies.
Mode of breast cancer detection was defined on the basis of self reported data. The remarkably low percentage of women having undertaken mammography within an organized screening program discouraged us from relying on official records to confirm our data. Under these circumstances, misclassification bias cannot be excluded. However, evidence from a validation study of self reported screening mammography histories suggests that non differential rather than differential is a more likely type of error and that the related estimates might understate the effects of screening detection regarding breast cancer outcomes
Our study also has several strengths. Data on demographics and mode of breast cancer detection were collected using a specifically conceived questionnaire which was administered during face-to face interviews. Abstraction of medical records on (breast cancer) pathologic features, treatment and outcomes was carried out by a specifically trained medical assistant who worked in close collaboration with the oncologists who had prospectively followed the patients included in our analyses. This increases our confidence in the quality of the data collected.
In our analyses, we included data concerning a wide panel of molecular biomarkers. In particular, we were able to gather data on biomarkers such as Ki-67, CK 5/6, CK14 and EGFR which were not available in previous studies