IRVING, Tex., May 30, 2015 /PRNewswire/ -- Caris Life
Sciences®, a leading biotechnology company focused on
fulfilling the promise of precision medicine, today announced the
presentation of data from three studies that demonstrate the
utility of Caris Molecular Intelligence®, the company's panomic
comprehensive tumor profiling service, in facilitating comparisons
between tumors that share histological features. In separate
presentations at the annual meeting of the American Society of
Clinical Oncology (ASCO) in Chicago,
Ill., the studies showed how multi-platform tumor profiling
via Caris Molecular Intelligence revealed a similar genetic
landscape with limited differences in brain metastases in patients
with non-small-cell lung cancer (NSCLC), breast cancer and melanoma
when compared to the corresponding primary tumors, while also
highlighting molecular similarities and differences between
specific histological subtypes in endometrial, renal and ovarian
cancers.
Caris Molecular Intelligence is a multi-platform tumor profiling
service that includes gene sequencing (Next-Generation Sequencing
[NGS] and Sanger), protein
expression analysis (Immunohistochemistry [IHC]), gene copy number
and translocation analysis (Chromogenic or Fluorescence in
situ Hybridization [CISH or FISH]). Investigators used these
methods to compare the molecular profiles of brain metastases from
common tumor types, as well as the profiles of histologically
similar cancers, as a means to identify potential treatment
strategies that specifically target the biomarkers detected in
individual patients' malignancies.
"Multi-platform profiling is a tool that can enhance
understanding of tumor biology, not only by elucidating patterns of
gene expression in brain metastases and primary tumor sites, but
also by helping to identify areas of overlap as well as molecular
differences in cancers that are histologically similar," said
Joanne Xiu, Ph.D., Research
Scientist and Molecular Science Liaison at Caris Life Sciences, and
a co-investigator in all three studies. "The data presented at ASCO
show that detection of molecular similarities between different
tumor types may dictate similar treatment strategies, while subtle
differences between tumors with similar histological features may
call for different therapeutic approaches."
Brain Metastases Study
In a June 1 poster
discussion (abstract #2060), researchers presented data
demonstrating the genetic similarity of brain metastases in
patients with NSCLC, breast cancer and melanoma, compared to
primary tumors. Using Caris Molecular Intelligence, they profiled
5,391 NSCLC (including 293 brain metastases and 5,098 primary lung
tumors), 3,595 breast cancer (99 brain metastases, 3,496 primary
breast tumors) and 761 melanoma (101 brain metastases, 660 primary
skin malignancies) unpaired samples. The investigators found no
significant differences in 48 genes between brain metastases and
the primary tumor sites, except for PIK3CA in breast cancer,
which was mutated less frequently in brain metastases than in the
primary breast samples (10% vs. 26%, respectively; p =
0.02). In contrast, expression of topoisomerase 2A (TOPO2), TOPO1
and thymidylate synthase (TS), as well as amplification of
epidermal growth factor receptor (EGFR), were more prevalent in
brain metastases than in all three primary tumor sites.
"The limited differences in brain metastases are more consistent
with a linear progression model of cancer metastasis, by which the
metastatic capabilities of tumor cells develop at primary sites
following the accumulation of alterations, than with the so-called
parallel progression model, which argues that tumor cells
disseminate early and accumulate changes independently at the
secondary site," noted lead investigator Santosh Kesari, M.D., Ph.D., Professor of
Neurosciences at the University of California
San Diego (UCSD) School of Medicine, and Director of
Neuro-oncology at Moores UCSD Cancer Center. "Our data also suggest
that both primary tumors and brain metastases would respond to
similar chemotherapeutics, particularly those that effectively
penetrate the blood-brain barrier."
Clear-cell Carcinoma Study
Another poster
presented at ASCO (abstract #5595) suggests that clear-cell uterine
carcinomas (CCUCs) and clear-cell ovarian carcinomas (CCOCs) are
molecularly similar to each other but significantly different from
clear-cell renal carcinomas (CCRCs), even though all three
clear-cell subtypes appear similarly under a microscope.
"Clear-cell uterine carcinoma accounts for approximately 5% of
endometrial carcinomas and exhibit aggressive clinical behavior
with poor outcomes," explained Robert
DeBernardo, M.D., Gynecologic Oncologist in the Department
of Gynecologic Oncology and Director of Minimally Invasive Surgery
in the Obstetrics/Gynecology & Women's Health Institute at the
Cleveland Clinic. "Clear-cell ovarian cancers are a subtype of
epithelial ovarian cancers that are chemo-resistant, with a poorer
prognosis than other subtypes. Seventy percent of renal cell
carcinomas are clear-cell and respond to inhibitors of tyrosine
kinase and mTOR. We profiled these clear-cell carcinomas to
determine if they rely on similar molecular pathways, and to
identify subsets of patients that may benefit from different
therapies."
In their analysis of 139 CCUCs, 409 CCOCs and 94 CCRCs, Dr.
DeBernardo and colleagues reported that CCRCs had fewer mutations
in the mammalian target of rapamycin (mTOR) pathway (PIK3CA:
25% in CCUC, 40% in CCOC, 4% in CCRC) and the MAP kinase (MAPK)
pathway (KRAS: 14%, 11% and 0%, respectively). They also
observed VHL mutations in 47% of CCRCs but not in any of the
CCUCs or CCOCs. Estrogen receptor (ER) and progesterone receptor
(PR) expression were more common in CCUCs and CCOCs but rare or
nonexistent in CCRCs (ER: 35%, 8% and 0%, respectively; PR: 22%,
13% and 2%, respectively), while androgen receptor (AR) expression
was more common in CCRCs (7%, 5% and 26%, respectively). All three
clear-cell carcinoma types had some immune-positivity for the
programmed cell death protein 1 (PD-1; 73%, 47% and 68%,
respectively) or its ligand, PD-L1 (13%, 6% and 29%,
respectively).
"Our data suggest that blockade of the mTOR and/or MAP kinase
pathways may be important in clear-cell uterine and ovarian
carcinomas," Dr. DeBernardo commented. "For patients with
clear-cell renal carcinoma, anti-angiogenic agents are more likely
to be of benefit. The frequency of PD-1 and PD-L1 expression
suggests that immunotherapies warrant further investigation in
selected patients with clear-cell carcinoma. More studies are
needed to correlate these markers with sensitivity to
chemotherapy."
Study Comparing Ovarian Carcinosarcoma, Ovarian Serous
Carcinoma and Endometrial Carcinosarcoma
In a third
ASCO poster presentation (abstract #5560), Dr. DeBernardo and colleagues reported that
ovarian carcinosarcomas (OCS), a rare and aggressive malignancy
with limited treatment options, share molecular changes similar to
that of serous ovarian carcinoma (SOC). They used Caris Molecular
Intelligence to evaluate 110 OCS, 141 endometrial carcinosarcoma
(ECS, another tumor type with similar histology to OCS) and 1,587
SOC samples to explore the potential overlap in treatment
paradigms. TP53 was the most commonly mutated gene in all
three malignancies, appearing in 76.4% of OCS, 68.8% of ECS and 69%
of SOC. Alteration of the PI3K/AKT/mTOR and MAPK pathways were
similar in OCS and SOC but was less frequently altered in ECS;
these alterations included mutations in PIK3CA (7.6% and
2.3% vs. 22.2%, p < 0.001), FBXW7 (0% and 0.6% vs. 12.1%,
p < 0.001), PTEN (3.7% and 0.8% vs. 12%, p < 0.001) and
KRAS (5.2% and 5.0% vs. 13.5%, p < 0.001). For the
homologous recombination pathway, SOC and ECS were more likely than
OCS to have BRCA1 (20% and 18% vs. 9%) and BRCA2
mutations (18% and 27% vs. 12%). However, the differences were not
statistically significant. No difference in alteration of RB,
NOTCH, angiogenesis and FGFR pathways was noted among the three
cohorts. ER (14.6% and 25.1% vs. 53.1%, p < 0.001) and AR (18.8%
and 12.2% vs. 32.4%, p < 0.001) were expressed less frequently
in OCS and ECS than SOC, respectively. On the other hand,
expression of PR was more frequent in in OCS and SOC than in ECS
(26.5% and 30.5% vs. 20.9%, p < 0.001).
"Both SOC and OCS have significantly lower activity of the
PI3K/AKT/mTOR and MAP kinase pathways and higher progesterone
receptor expression than ECS," Dr. DeBernardo noted. "Treatments
that are active against SOC may be considered when treating
patients with OCS."
About Caris Life Sciences®
Caris Life Sciences® is a leading biotechnology company focused on
fulfilling the promise of precision medicine through quality and
innovation. Caris Molecular Intelligence®, the company's healthcare
information and comprehensive tumor profiling service with more
than 70,000 patients profiled, provides oncologists with the most
clinically actionable treatment options available to personalize
cancer care today. Using a variety of advanced profiling
technologies to assess relevant biological changes in each
patient's tumor, Caris Molecular Intelligence connects biomarker
data generated from a tumor with biomarker-drug associations
supported by evidence in the relevant clinical literature. Since
2009, Caris has tracked clinical and outcome data for certain
patients undergoing tumor molecular profiling, for which Caris has
observed that patients treated with drugs consistent with their
molecular profile show a significant increase in overall survival.
The company is developing its Carisome® TOP™ technology, a
revolutionary and proprietary blood-based platform for the
development of novel therapeutics, drug delivery and drug target
identification. The technology is also being developed for
diagnosis, prognosis, and theranosis of cancer and other complex
diseases. Headquartered in Irving,
Texas, Caris Life Sciences offers services throughout
Europe, the U.S., Australia and other international markets. To
learn more, please visit www.CarisLifeSciences.com.
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