New Universal Breast Cancer Marker Predicts Recurrence and Clinical Outcome
Reporting online in the American
Journal of Pathology, researchers from the Kimmel Cancer Center at Jefferson
have implicated the loss of a stromal protein called caveolin-1 as a major new
prognostic factor in patients with breast cancer, predicting early disease
recurrence, metastasis and breast cancer patient survival.
The absence of caveolin-1 in the stroma
also appeared to be a marker for drug resistance in patients receiving
tamoxifen, according to Michael Lisanti, M.D., Ph.D., professor in the
departments of Cancer Biology, Medical Oncology and Biochemistry and Molecular
Biology at Jefferson Medical College of Thomas Jefferson University.
According to Dr. Lisanti, who is also
director of the Jefferson Stem Cell Biology and Regenerative Medicine Center at
the Kimmel Cancer Center, caveolin-1 is expressed by cells in the stroma called
fibroblasts, which are present in the connective tissue surrounding cancer
cells. When cancer cells arise, the fibroblasts stop making caveolin-1.
“The idea that a prognostic biomarker is
present in the stroma rather than the epithelial cancer cell is
paradigm-shifting,” Dr. Lisanti said. “Importantly, these findings could be
developed into a diagnostic test that would not require DNA-based technologies.
This inexpensive and cost-effective test would allow doctors to identify
high-risk breast cancer patients at diagnosis and treat them more aggressively.”
Dr. Lisanti, along with first author
Agnieszka Witkiewicz, M.D., assistant professor of Pathology, Anatomy and Cell
Biology at Jefferson, and other colleagues analyzed breast tissue samples from
154 women diagnosed with breast cancer. All samples were obtained from the
University of Michigan. They used three tissue cores from each patient tumor
sample, and analyzed each core for stromal caveolin-1 using immunohistochemistry
staining.
The absence of stromal caveolin-1 was
strongly associated with other predictors of more aggressive disease, such as
higher tumor stage and lymph node metastasis. Among each subgroup of patients –
grouped by prognostic factors such as hormone status, disease stage or lymph
node status – a loss of stromal caveolin-1 remained the single strongest
predictor of breast cancer patient outcome.
Also of note, among patients with
ER-positive breast cancer who were taking tamoxifen, a loss of stromal
caveolin-1 still predicted recurrence and poor clinical outcome. As many as 40
percent of patients who take tamoxifen in this setting relapse despite its
significant effect on survival when used in the early stages of the disease.
“Resistance to tamoxifen is thought to be
an epithelial ‘cancer cell’ phenomenon, but we show here that it is clearly a
‘stromal’ phenomenon,” Dr. Lisanti said.
Progression-free survival (PFS) was also
affected by the loss of stromal caveolin-1. Overall, the PFS in patients with an
absence of stromal caveolin-1 was reduced by approximately 3.6-fold. In
lymph-node positive patients, the difference in PFS was especially pronounced:
The approximate five-year survival rate for patients positive for stromal
caveolin-1 was 80 percent, vs. 7 percent for patients negative for stromal
caveolin-1. That is an approximate 11.5-fold reduction in five-year PFS.
“This marker serves not only as a
prognostic marker, but also as a means of therapeutic stratification,” Dr.
Lisanti said. “We can identify this marker at breast cancer diagnosis, which is
important because high-risk patients would benefit from more aggressive
treatment and/or anti-angiogenic therapy.”
In an additional study, published online
in Cancer
Biology & Therapy, the researchers also found that the loss of
stromal caveolin-1 in ER-positive non-invasive breast cancers called ductal
carcinoma in situ (DCIS) serves as a biomarker for progression to invasive
breast cancer.
“This marker was highly predictive of
development of invasive breast cancer in patients with DCIS,” said Gordon
Schwartz, M.D., a professor of Surgery at Jefferson, who was involved with the
DCIS study. “We have been searching for a marker to separate patients with DCIS
who require further treatment from those who might be treated with lumpectomy
alone. If this marker can be validated further, then high-risk patients may be
identified and treated to prevent the development of an invasive breast cancer.
Those at low-risk would be spared from radiation therapy and/or mastectomy.”
The prognostic value of a loss of
caveolin-1 has now been validated in three independent patient populations. In
an editorial appearing online in Cell
Cycle, the researchers propose a “stromal” classification system that
divides patients into high-risk and low-risk groups based on caveolin-1 status.
Patients without caveolin-1 should be offered more aggressive therapy in
addition to standard treatments.
“These are significant findings that do
have to be validated in prospective breast cancer clinical trials,” said Richard
Pestell, M.D., Ph.D., director of the Kimmel Cancer Center at Jefferson, who was
also involved with the studies. “However, we should start taking the breast
tumor stroma into our clinical considerations sooner, rather than
later.”
Note: Dr. Lisanti serves as
Editor-in-Chief of the American Journal of Pathology. A guest editor acted as
editor-in-chief for the manuscript referenced in this press release. No person
at Thomas Jefferson University was involved in the peer review process or final
disposition for this article.
Media Only Contact:
Emily Shafer
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 5/14/2009