CORRESPONDENCE

Re: Role of Detection Method in Predicting Breast Cancer Survival: Analysis of Randomized Screening Trials

Eugenio Paci, Antonio Ponti, Emanuele Crocetti, Marco Zappa, Nereo Segnan

Affiliations of authors: Unit of Clinical and Descriptive Epidemiology, Centre for Study and Prevention of Cancer, Research Institute of Tuscany Region, Florence, Italy (EP, EC, MZ); Unit of Epidemiology, Centre for Prevention of Cancer, Turin, Italy (AP, NS)

Correspondence to: Eugenio Paci, MD, Epidemiology Unit, Via di San Salvi 12, Florence, Italy 50135 (e-mail: e.paci{at}cspo.it).

Method of detection is an independent prognostic factor for breast cancer survival, according to the analysis of the Health Insurance Plan (HIP) and Canadian trials presented by Shen et al. (1); i.e., there is an increased likelihood that mammography screening is detecting slowly growing, indolent tumors, compared with aggressive tumors diagnosed in clinical settings. However, the authors did not perform a survival analysis by intention to treat, with or without adjustment for tumor characteristics; this analysis would have provided an estimate corrected by selection that resulted from nonattendance. In screening population-based trials, but not in the Canadian trials that used volunteers, nonattendance is a well-known, potential indicator of selection bias for breast cancer mortality. Survival rates of patients with interval breast cancers vary among studies and are very dependent on the working definition of this kind of tumor.

Nonrespondent patients with breast cancer had worse survival than the comparison or control group in U.K. trial (2) and in the Two-County study (TCS) (3). Only about one-third of the survival benefit for patients with screen-detected breast cancer was explained by adjustment for tumor characteristics (in the U.K. trial by size and lymph node status and in the TCS also by tumor grade). Similar data have been published for an observational study of service screening in the Netherlands (4).

In the evaluation of service screening in Italy in which the registry-based records of 4444 patients with breast cancer were studied (5), we performed an intention-to-treat analysis between invited and noninvited patients. The hazard ratio (HR) of dying from breast cancer increased, after adjustment for tumor size, lymph node status, and grade, from 0.73 (95% confidence interval [CI] = 0.61 to 0.87) to 1.03 (95% CI = 0.85 to 1.24) (Table 1). In a parallel analysis by diagnostic modality, we obtained a higher hazard ratio for nonrespondents of 1.23 (95% CI = 0.98 to 1.55) than for noninvited women, after adjustment for tumor characteristics.


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Table 1.  Cox models of the risk of dying for invasive breast cancer by method of detection, with or without adjustment for tumor size, lymph node status, and grade: service screening in Italy (n = 4444)*

 
Baker et al. (6) suggested a causal estimate of the screening effect in which never-attenders have the same probability of cancer death in the screened and control groups; i.e., the probability of dying should be the same in the screened group (where it is observed) and in the control group (where can be estimated). In contrast, attenders would have a higher probability of surviving than an average patient in the control group, also in the absence of the intervention. If the survival rate for nonattenders is worse than the average survival rate of the control groups, then the hazard ratio for screen-detected breast cancers compared with that of the causally corrected reference is moving toward unity.

Why should we study a subgroup with a different probability of dying that is not entirely explained by tumor characteristics but is related to compliance to the screening invitation? Important reasons for compliance to screening may include a differential opportunity for effective treatment and/or differential levels of comorbidity (4) or of socioeconomic status (7). Nonrespondents may have less access to treatment or may tend to seek treatment less promptly. In some instances, patients with screen-detected breast cancers might have been preferentially referred for higher quality treatment or more prompt diagnosis in the absence of screening. These factors are only partially related to the stage of the disease at presentation.

In conclusion, other, more recent randomized trials and observational screening trials reported results that differ from the HIP and Canadian trials. The survival benefit associated with screen-detected breast cancers, if any, might be better estimated by 1) analyzing recent screening studies, 2) adopting an intention-to-treat analysis and comparing the unadjusted and adjusted (for prognostic covariates) estimates of probability of survival, and 3) using a model in which the selection related to nonattendance (or clinical detection) is taken into account when the estimate of the benefit is calculated.

REFERENCES

(1) Shen Y, Yang Y, Inoue LY, Munsell MF, Miller AB, Berry DA. Role of detection method in predicting breast cancer survival: analysis of randomized screening trials. J Natl Cancer Inst 2005;97:1195–203.[Abstract/Free Full Text]

(2) Moss SM, Ellman R, Coleman D, Chamberlain J. Survival of patients with breast cancer diagnosed in the United Kingdom trial of early detection of breast cancer. United Kingdom Trial of Early Detection of Breast Cancer Group. J Med Screen 1994;1:193–8.[Medline]

(3) Duffy SW, Tabar L, Fagerberg G, Gad A, Grontoft O, South MC, et al. Breast screening, prognostic factors and survival—results from the Swedish two county study. Br J Cancer 1991;64:1133–8.[ISI][Medline]

(4) Ernst MF, Voogd AC, Coebergh JW, Roukema JA. Breast carcinoma diagnosis, treatment, and prognosis before and after the introduction of mass mammographic screening. Cancer 2004;100:1337–44.[CrossRef][ISI][Medline]

(5) Paci E, Ponti A, Zappa M, Patriarca S, Falini P, Delmastro G, et al. Early diagnosis, not differential treatment, explains better survival in service screening. Eur J Cancer. In press, 2005.

(6) Baker SG, Kramer BS, Prorok PC. Statistical issues in randomized trials of cancer screening. BMC Med Res Methodol 2002;2:11.[CrossRef][Medline]

(7) Lagerlund M, Bellocco R, Karlsson P, Tejler G, Lambe M. Socio-economic factors and breast cancer survival—a population-based cohort study (Sweden). Cancer Causes Control 2005;16:419–30.[CrossRef][ISI][Medline]


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