Researchers from the University of California, San Francisco, have identified a specific biological response to cellular stress that may help predict the likelihood of future tumour formation of the most common, non-invasive form of pre-malignant breast cancer-- ductal carcinoma in situ, or DCIS.
According to the study, the information could potentially be used in a clinical setting to determine which women should receive more or less aggressive therapy when initially diagnosed with DCIS.
By identifying this particular biological response in patients, physicians may now be able to predict subsequent tumour formation years before it actually occurs.
"We were very excited by the results. Until now, little has been known about the molecular pathways that may cause a differential risk in women diagnosed with this type of breast pre- malignancy," said senior author Thea Tlsty, PhD, professor of pathology and co-leader of the Cell Cycling and Signaling Program of the UCSF Comprehensive Cancer Center.
DCIS is a type of breast cancer where cancer cells form inside the milk ducts of the breast but have not spread to surrounding breast tissue. DCIS accounts for nearly 25 percent of all breast cancer diagnoses.
Women diagnosed with DCIS today are often offered a gamut of treatment options that extend from a full mastectomy to watchful waiting.
"Conversely, since some women still get subsequent invasive carcinomas following these therapies, we may be under-treating a group of women diagnosed with DCIS," Tlsty said.
Approximately 12-15 percent of women diagnosed with DCIS develop a subsequent invasive tumour within 10 years after undergoing surgical lumpectomy.
As observed in the study, it is well recognized that normal cellular responses to stress are important barriers to cancer formation and therefore also provide researchers with molecular candidates to help identify lesions that will not progress to a malignancy.
To determine if stress-associated biomarkers in this response could provide insight into the likelihood of subsequent tumour formation in DCIS, the researchers examined several biomarkers in biopsies of DCIS tissue both in isolation and in conjunction to determine their effects.
They found that the presence of high amounts of two biomarkers, p16 and COX-2, played a critical role in the biological response to cellular stress. In particular, they found that tumours with high p16 and/or high COX-2 in the absence of cell proliferation reflected correct stress activation and a protective response to cellular stress.
"This phenotype begins to identify women less likely to have a subsequent tumor event after a diagnosis of DCIS. It supports the hypothesis that the senescent program is a barrier to tumor growth," Tlsty said.
In a second group, DCIS tissue with high p16 and/or high COX-2 in the presence of ongoing cell proliferation corresponded to a short-circuited response to cellular stress. The lesions in this group had lost functional p16/retinoblastoma (Rb) signaling, allowing cells to proliferate unchecked and thus likely to lead to subsequent tumour formation. This finding positively identified the Rb pathway as a key regulator in these responses.
According to Tlsty, study findings showed that the expression of biomarkers indicative of the short-circuited response was also a defining characteristic of basal-like invasive tumours, a more aggressive form of breast cancer, which was a striking discovery.
"We found that the expression of biomarkers of a stress-associated response is conditional and can reflect two distinct processes distinguished by the absence or presence of a proliferation of cells. We anticipate that these phenotypes have the potential to accurately predict the occurrence of future tumor events in women diagnosed with DCIS," Tlsty added.
The biological phenotypes identified in this study are now being validated in a large, independent study of women diagnosed with DCIS. Initial results are expected within the next year.
The study is the cover story of the November 13, 2007 issue of "Cancer Cell."