Interval breast cancers were larger, of more advanced stages, more poorly differentiated, more likely to have lymph node involvement and had a higher proliferation rate compared with matched screen-detected cancers, according to a study published in the May issue of the Journal of the National Cancer Institute, leading the authors to call for more sensitive screening modalities and different approaches for early detection of fast-growing tumors.
Interval cancers are a mixed group of tumors in which recognizable features of the tumor are not detected at screening for technical or interpretative reasons (missed interval cancers) or are not detectable at screening (true interval cancers).
Previous research has shown that interval cancers are more likely to be larger, diagnosed at stage 2 or higher and have lymph node involvement compared with screen-detected cancers. Other characteristics of interval cancers, such as vascular invasion and histological grade, are associated with an unfavorable prognosis.
Canadian researchers hypothesized that true and missed interval cancers would differ on prognostic features compared with screen-detected cancers and designed a retrospective study to compare these characteristics and evaluate the effectiveness of screening mammography.
The researchers leveraged a sub-cohort of the 431,480 women screened through the Ontario Breast Screening Program (OBSP) between Jan. 1, 1994 and Dec. 31, 2002. OBSP consists of biennial screening and clinical breast exam.
The study evaluated characteristics of 87 missed interval cancers, 288 true interval cancers and 450 screen-detected cancers matched to the interval cancers.
The groups differed in several key areas, according to Victoria A. Kirsh, PhD, of Cancer Care Ontario, in Toronto. “Mammographic density of 75 percent or greater was more frequent among women who were diagnosed with an interval cancer [missed 2.5 percent, true 7.2 percent] compared with those who were diagnosed at screening [1.9 percent] as previously reported.”
Women diagnosed with interval cancers were more likely to report current hormone therapy use and previous diagnosis of benign breast disease.
“Interval cancers were larger, of more advanced stage, more poorly differentiated, more likely to have lymph node involvement and had a higher proliferation rate,” wrote Kirsch. The researchers noted additional adverse prognostic features of true interval cancers including estrogen receptor (ER) and progesterone receptor (PR) negative status and not being of ductal morphology.
Kirsch and colleagues offered a pair of possible explanations for the difference in prognostic features. One possibility is that true interval cancers proliferated rapidly and became palpable in between screening. The second is that true interval cancers are less easily detected by mammography.
The researchers also noted the significance of other findings. “[E]xtensive mammographic density—which may mask the tumor from detection—is strongly positively associated with the risk of interval-surfacing breast cancer in our study population,” wrote Kirsh.
In addition, the higher mitotic count of interval tumors indicates that true interval cancers are rapidly growing tumors. “Almost 30 percent of the true interval cancers had a high mitotic index compared with 11 percent of the screen-detected cancers.”
The study also reinforced earlier findings reporting overrepresentation of negative ER status in interval-detected cancers relative to screen-detected cancers at almost 30 percent in the true interval group vs. 15 percent in the screen-detected group.
“Our findings lend support to the hypothesis that true-interval detected cancers are either particularly biologically aggressive or may indicate a greater likelihood of mammographic masking among ER-negative tumors,” wrote Kirsh et al.
The researchers attributed the aggressive tumor features of interval cancers to multiple causes: a rapid proliferation rate, delayed diagnosis and reduced tumor detection on mammograms. “This suggests a need for further advancement in imaging technologies to detect certain types of breast carcinomas and different approaches for early detection of fast-growing tumors.”