A new positive prognostic indicator found in human solid tumors by metagene analysis: IGKC presence

1. Immunoglobulin Kappa C
Prognostic markers for cancer: Background and Discussion
Charles Hall

2. Outline
 Background
 Treatment Options
 Proteomics
 IGKC – just one of many prognostic markers
 Schmidt et al. Paper
 Discussion

3. Hallmarks of Cancer
 Viability
 8 Hallmarks and 2 characteristics  Motility
 Inhibitors  Proliferation
 Cytostasis and differentiation

4. Tumor Microenvironment

5. Staging
 Tumor, Node, Metastasis
System most common
 Clinical vs. Pathologic
 Exceptions: Brain, Bone
Marrow, Blood and Gynecologic
cancers
 Treatment decisions and
Progression

6. Tumor Grade
 Differentiation
 Microscopic
determination
 Prognostic value
 Important for Breast  Systems specific to each
Cancer cancer type
 Treatment  Predictive of growth and spread

7. Immune Score
 New Concept (Finalizes in December 2012)
 Incorporates Tumor Microenvironment
 IHC to characterize tumor infiltrates for staging
 Seeks to enhance prediction of prognosis and
response to treatment
 Infiltrates – center of tumor, invasive margins, adjacent
lymphoid islets
 Ultimate Goal: Density and location of immune cells
within tumor (influence survival/relapse risk)

8. Radiation Oncology
 5R’s vs. 6 hallmarks
 Downstream effects
on choice of
treatment with
radiation

9. Proteomics
 Methods
Gel Based Fluorescent beads
Mass Spec Array Based
 Technology
MALDI
SILAC
LC-MS
Ab Arrays
Luminex (Fluor)

10. Markers
 Positive:
IGKC, single ER or
PR, SEC14L2
 Negative:
Her2/neu+, Ki67, p53
, BRCA1/2, VEGF, C
yclin E, Triple
negative cells, IDH2
and CRABP2
Pancreatic: Ki67, Smac Ovarian: CD133, ALDH
Prostate: PSMA, Her2/neu CRC: SATB2, BRAF
Esophageal: p53, p73 NSCLC: Survivin

11. IMMUNOGLOBULINS HAVE 4 POLYPEPTIDE CHAINS
2 gamma or kappa
light chains on
each Antibody
2 Identical H(eavy) chains
2 Identical L(ight) chains

12. Schmidt et al.

24. Hallmarks of IGKC
 First Humoral Immunity Component studied
 Predictive of Metastasis-Free Survival
 Response to chemotherapy (anthracycline)
 Simplifies analysis from B cell metagene (60) to IGKC (1)
 TA-specific Antibodies (?) – ADCC or Signalling
 Plasma cell infiltrates vs. NK or T or Monocytes
 Immune Score alternative to AJCC method
 Tumor Clearance - B cell vs. T cell importance

25. Whiteside and Ferrone Commentary - Figure 1

26. Conclusions
 Positive prognosis and positive response to
neoadjuvant anthracycline chemotherapy treatment
 Considered first immune gene signature relevant to
prognosis and treatment (others proliferation)
 Implicates Humoral Immunity involved in tumor
microenvironment (not just cell-mediated)

27. Discussion
 This paper distills down multiple metagene studies for
their results in finding a representative marker for
positive prognosis in the case of three forms of cancer.
What are some other prognostic indicators (negative or
positive), either discussed in the course of the paper or
from a quick search of the literature, that are commonly
used in cancer observation for either treatment or
survival?

28. Question 2
 The Whiteside commentary that accompanied the
paper described the use of IGKC as a “silver bullet” of
sorts for genetic analyses where only one gene
representative of metastases free survival can be
studied representative of a whole 60-gene study of the
B-cell metagene. Is this a wise method to add to the
current practices of staging with an immune score
based on IGKC? Are there other factors to consider
that might call for other options in this case?

29. Question 3
 With our recent lectures focusing on monoclonal
antibody treatments of cancer (humoral immunity
derived) and induced CTA expression as a method to
educate T cell-mediated immunity enhanced by
adoptive cell transfer, is there one system that seems
more effective in immunotherapy at this point, humoral
vs. cell-mediated, or is it too soon to know because
they are both in their infancy of study as treatment
options?

30. Question 4
 Concerning the ideas of merging current staging
techniques for the characterization of tumors with the
immune markers discussed in the paper, Does this
paper make a significant case for the “emerging role of
the immune system as a clinically relevant hallmark of
cancer biology” from the standpoint of this biomarker?

31. Question 5
 The Schmidt paper alludes to the hypothesis that
“chemotherapy does not only exert a direct cytotoxic
effect, but at the same time enhances the antitumor
immune response.” This thought is not new but further
substantiated by the correlation results of the study of
people with IGKC showing a positive response to
anthracycline neoadjuvant chemotherapy. Is it likely to
be useful in determining other treatment plans in
patients with adenocarcinoma or just in survival
outcomes?

32. Closing Thoughts…
 Proteomics
 microRNA’s
 Hallmarks
 Radiology & Chemotherapy
 Cancer Registry