Download Tumor Cellularity and Dose Level

Reduced Tumour RNA Integrity
in Response to Chemotherapy in
Breast Cancer Patients
Northern Health Research Conference
May 28, 2010 Sudbury, ON
Disclosure Statement
• Patents related to the findings
presented in this seminar have been
filed and are entering the national
phase in Canada, the U.S.A., Europe,
Australia, and Japan
• A company (RNA Diagnostics, Inc.)
will commercialize the intellectual
properties associated with the patent,
for which I am a shareholder and serve
as its Chief Scientific Officer
Locally Advanced Breast Cancer
• A breast cancer that has progressed locally but has
not yet spread outside the breast and local lymph
nodes
• Includes large breast tumors (more than 5
centimeters in diameter), those that involve the skin
of the breast or the underlying muscles of the chest
wall, and cancers that have extensive involvement of
the local lymph nodes (in the axilla or in the soft
tissues above and below the collarbone)
• Also includes inflammatory breast cancer, a rapidly
growing type of cancer that makes the breast appear
red and swollen, without a distinctive breast lump
Treatment of Locally
Advanced Breast Cancer
• For most women with locally advanced breast
cancer, chemotherapy is the first component of the
treatment, before surgery (aka “neoadjuvant
chemotherapy”)
• Typically, patient tumours are treated with an
anthracycline (doxorubicin or epirubicin) in concert
or followed by a taxane (paclitaxel or docetaxel)
• In some countries pre-operative chemotherapy has
become standard for treatment of most breast
cancers, since survival rates appear to be similar if
chemotherapy precedes surgery
Typical Response Rates for
Treatment of Locally Advanced
Breast Cancer by Chemotherapy
• Typically ~30% of patients with locally
advanced breast cancer have a clinical complete
response to neoadjuvant chemotherapy
(complete disappearance of all detectable
malignant disease in breast by palpation)
• In contrast, only ~10% of patients with locally
advanced breast cancer have a pathologic
complete response to neoadjuvant
chemotherapy (complete eradication of disease
at the cellular level)
Utility of a Biomarker of
Response to Chemotherapy
• The low rates of clinical complete response and
pathologic complete response in patients with
inflammatory breast cancer indicate that vast
majority of these patients will experience disease
recurrence and/or progression of disease
• Thus, it would be highly useful to be able to monitor
response to chemotherapy in inflammatory breast
cancer patients
• If tumours show a lack of response to chemotherapy,
then chemotherapy (and its side effects) can be
discontinued and downstream options such as
surgery, radiation therapy, or other chemotherapy
drugs could be quickly considered
Tumour RNA Quality (Integrity) as a
Biomarker of Chemotherapy Response
• Unlike DNA, RNA is much less stable in normal
and tumour cells
• Recent evidence suggests that chemotherapy
agents may induce RNA damage and the
production of RNA-degrading enzymes
• It is possible that a reduction in tumour RNA
integrity could serve as a useful biomarker of
chemotherapy response in patients with
inflammatory breast cancer.
The RNA Integrity Number (RIN): A quantitative
measure of RNA quality, not quantity
NCIC-CTG MA.22 Clinical Trial
• Patients with locally advanced breast cancer are
typically treated with anthracyclines followed by
taxanes
Popular Regimens:AC→T, EC →T,
FEC 100 →T (all q3wX6)
• However, <40% of patients respond to taxanes
after anthracycline-based chemotherapy
• MA.22 is assessing whether anthracycline/taxane
chemotherapy may have greater therapeutic
efficacy if the drugs are co-administered rather
than given sequentially
Tumour RIN Values of 50 MA.22
Patients (Pre-, Mid-, And Post-Treatment)
Dose Level 1
Dose Level 2
Dose Level 3
Dose Level 4
Dose Level 5
Dose Level 6
Dose Level 7
(p=0.05)
P-value from one-way Analysis of Variance (ANOVA)
(p=0.12)
Relationship Between Tumour RIN
and Tumour Cellularity (Extent)
Plot of
Tumour
RIN Versus
Tumour
Cellularity
(Extent) for
Each
Patient in the
MA.22
Clinical
Trial
Tumour RIN
is NOT a
surrogate
measure of
tumour
cellularity
RIN and Tumor Cellularity by Response to Clinical Treatment
Factors Assessed
Baseline
P-value1
Midtreatment
P-value1
Posttreatment
P-value1
Maximum RIN and Dose Level
0.61
0.05
0.12
Maximum RIN and Best Clinical
Response (CR;PR/SD/PD)
Maximum RIN and Pathologic
Response (CR;PR/SD/PD)
Tumor Cellularity and Dose Level
0.12
0.61
0.64
0.96
0.01
0.28
0.14
0.77
0.78
Tumor Cellularity and Best Clinical
Response (CR;PR/SD/PD)
Tumor Cellularity and Pathologic
Response(CR;PR/SD/PD)
0.86
0.95
0.91
0.72
0.68
0.01
1P-value
from one-way Analysis of Variance (ANOVA).
• Correlation between low mid-treatment tumour RIN values and drug dose level
suggests that tumour RIN may clearly be a biomarker of drug response
• Data suggests that mid-treatment tumour RIN determinations can predict posttreatment pathologic complete response
• Pathologist cannot predict whether patient will undergo pathologic
complete response by examining tumour cellularity mid-treatment
Future Perspectives Related to the
Use of the RIN as a Biomarker
of Chemotherapy Response – Part I
• We have heard that Dr. John Bartlett of the University of
Edinburgh in the UK has validated our findings in an
independent cohort of breast cancer patients treated with
an anthracycline-based chemotherapy regimen
• Our findings will hopefully be further validated in an
additional independent cohort of breast cancer patients
treated with various chemotherapy regimens in
collaboration with I-Spy Clinical Trial in the U.S.A.
• The I-SPY trial will also assess how soon after treatment
statistically significant reductions in tumour RIN can be
observed, which predict pathologic complete response in
cancer patients
Future Perspectives Related to the
Use of the RIN as a Biomarker
of Chemotherapy Response – Part II
• Future studies will also focus on determining whether
similar reductions in tumour RIN can be observed in
patients with other solid and nonsolid tumours that are
being treated with a variety of chemotherapy drug classes
• A new company (RNA Diagnostics, Inc.), Inc. has
negotiated an exclusive license to the IP associated with
the patent. It will fund further validation studies and
productize what we are calling the “RNA Disruption
Assay” or RDA for measuring chemotherapy response in
cancer patients.
A New Research Grant!
• The Cancer Research Fund of the Ontario Institute for
Cancer Research has awarded a $381,847 grant to further
these promising studies
• Principal Investigator: Dr. A. Parissenti of NOSM/LU/SRH
• Co-investigators
Dr. D. Maclean, graduate student S. Fabris, animal studies
Dr. M. Trudeau, Sunnybrook Hospital, MA.22 clinical trial
Dr. L. Esserman, UCSF San Francisco, I-SPY clinical trial
Drs. L. Shepherd, J. Chapman, NCIC Clinical Trials Group
Acknowledgements
Judy-Anne W. Chapman2, Harriette J. Kahn3, Baoqing
Guo1, Lei Han2, Patti O’Brien2, Mark P. Clemons4,
Roberta Jong3, Rebecca Dent3, Barbara Fitzgerald4,
Kathleen I. Pritchard3, Lois E. Shepherd2, Stacey Santi1,
and Maureen E. Trudeau3
1Regional
Cancer Program, Sudbury Regional Hospital,
Sudbury, ON, 2National Cancer Institute of Canada
Clinical Trials Group, Queen’s University, Kingston,
ON, 3TorontoSunnybrook Health Sciences Centre,
Toronto, ON, 4Princess Margaret Hospital, University
Health Network, Toronto, ON