Poster Discussion III

Robert G. Maki, MD PhDMemorial HospitalNew York, NY, USA

Focus on just a few of the quality posters from this session

• Basic Science– 34824 Leiomyosarcoma phosphokinome (El Sayadi)

• Neoadjuvant therapy– 34844 Volume change after neoadjuvant chemo in extremity sarcomas

(Lackman)– 35131 Preop imatinib for GIST (Trent)

• Novel therapeutics– 35010 Apomab phase II (Chawla)– 34863 HDAC inhibitors and chemotherapy (Lopez)

• Controversy– 35001 Pleomorphic RMS therapy (Whelan)– 35060 Three EOI osteosarcomas studies (Whelan)

The Theatre

• 1st successful theatre (2nd overall, after the Red Lion), built 1576 by James Burbage and John Brayne in Shoreditch

• After Thomas Nashe's play, Isle of Dogs, all London theatres were closed in summer of 1597. The Theatre did not reopen.

• Dismantled by carpenter Peter Street in 1598, parts became• …the Globe Theatre: 1599• 6 August 2008: Portions found again in an excavation on New Inn

Broadway

The Theatre, 1576

Question 1

How do you distinguish aneuploid sarcomas of a given histology?

34824 Leiomyosarcoma phosphokinome (page 71 of program)

• El Sayadi et al. examined 13 LMS frozen samples with a multiplex (652 protein) kinase assay (Kinexus)– ~380 protein-specific antibodies– 270 phosphorylation site specific antibodies

• Elevated levels of PKC, Tyro3, MSH2 in LMS vs normal muscle• Two clusters of LMS: One more like normal muscle, another

with distinct Rb and other phosphoprotein expression• Correlation to CGH and miRNA arrays underway• Could well have prognostic or predictive consequences for

therapy

The variability of leiomyosarcomas

• Aneuploid karyotype• Somewhat different pattern of metastasis based on

anatomic primary site• Different sensitivity to chemotherapy: Uterine >

retroperitoneum/extremity > GI• How can we predict who will do well and who might

benefit from adjuvant chemotherapy?

Henry V, III, vi (1598-99)

Fluellen: By your patience, Aunchient (Ensign) Pistol. Fortune is painted blind, with a muffler afore her eyes, to signify to you that Fortune is blind; and she is painted also with a wheel, to signify to you, which is the moral of it, that she is turning, and inconstant, and mutability, and variation: and her foot, look you, is fixed upon a spherical stone, which rolls, and rolls, and rolls: in good truth, the poet makes a most excellent description of it: Fortune is an excellent moral.

• We have much to learn regarding the biological heterogeneity of even the most common of the sarcomas we treat.

Question 2

Can we use something other than RECIST to determine radiological outcome for

sarcoma patients?

34844 Lackman et al.: MRI tumor volume, neoadjuvant chemotherapy, and outcome (p. 71)

• 3-dimensional MRI measurements used • 12 month follow up minimum, pts from 1998-2007• Doxorubicin based therapy employed in 90% of patients• RT typically given after chemotherapy, before surgery• Definitions employed:

– Progression ≡ Tumor volume increase ≥ 10%– Response ≡ Tumor volume decrease ≥ 10%– Stable ≡ Everything else

• N = 41 of 92 met criteria for analysis– MFH (12), Lipo (9), Synovial (7), NOS (5), LMS (4)– Most missing patients excluded for lack of volume data

Outcomes

• Median follow up 41.5 months (12-118).• n = 41 :

– Response 22 (54%)– Progression 15 (36%)– Stability in 4 (10%)

• Median volume change: -19 cm3(-18%); mean +134 cm3 (+20%)• LR: 4 (2 responders, 2 progressors)• Mets: 8 (4 from each group)• Death: 8 (6 from progression group, 1 from response and 1 from stable

group)• Patients with poor outcome had shorter OS than other two groups (p=0.02

Cox, p=0.005 K-M)• DFS similar for both groups (p~0.45-0.5)• Degree of tumor necrosis did correlate with outcome

Volume change and OS

p=0.01

No correlation between volume change and necrosis

*One outlier (85%,+931%) is not shown on the graph.

R2 = 0.003

-100%

-50%

0%

50%

100%

150%

200%

250%

0% 20% 40% 60% 80% 100%

Percent Histopathologic Tumor Necrosis

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Comments

• We’ve got the information, why not use it?!

• Would be interesting to see sensitivity analysis to see how volume change (percentage) would affect these cutoffs

• Correlation with PET or DCE MRI would also be intriguing

King John, V, vii (1595-6)

Ay, marry, now my soul hath elbow-room; It would not out at windows nor at doors. There is so hot a summer in my bosom, That all my bowels crumble up to dust: I am a scribbled form, drawn with a pen Upon a parchment, and against this fire Do I shrink up.

• Even those these changes are small (3√10 = 2.15 mm), they appear to be meaningful, and are worth examining with respect to PET and other metrics of response in a larger study.

Question 3

How quickly do GIST patients respond to imatinib in the neoadjuvant setting?

35131 Trent et al.: Preop imatinib for GIST (p. 87)

• n=20 patients randomized to 3, 5, or 7 days of imatinib preop at 600 mg oral daily, then completed 2 years therapy.

• Efficacy evaluated by PET, dynamic contrast CT, TUNEL, DFS

• ~70% of patients showed signs of PET or CT response• Apoptosis increased mean 12% on Rx (0-33%)• Median DFS in this cohort: 44 mo• Tumor size predicted recurrence risk (p=0.02)

Disease free survival curve

The Tempest, II, i (approx. 1611)• Antomo:

. . . Who's the next heir of Naples?• Sebastian:

Claribel.• Antonio:

She that is Queen of Tunis; she that dwellsTen leagues beyond man's life; she that from NaplesCan have no note, unless the sun were post—The Man i' th' Moon's too slow—till new-born chinsBe rough and razorable; she that from whomWe all were sea-swallow'd, though some cast again(And by that destiny) to perform an actWhereof what's past is prologue; what to come,In yours and my discharge.

• We will see further data fairly regarding the utility of adjuvant imatinib

Question 4

What are promising new combinations of targeted and cytotoxic systemic

therapeutics?

34863 Lopez et al. Synergy of HDAC inhibitors and chemotherapy (p. 72-73)

• HDAC inhibition interesting novel therapeutic in synovial and other sarcomas (T. Nielsen, Vancouver)

• PCI-24781 examined against 4 STS cell lines• 44 genes showed significant change in expression at mRNA

and protein levels, including RAD51 (reduction) • Chemotherapy + HDACi more effective than either alone• Interesting owing to the central role of RAD51 in repairing

DNA damage (double strand DNA breaks)• One of a family of proteins, any others affected?• Interacts with BRCA1 and BRCA2; are these affected?

HDAC vs. sarcoma cell lines (colony formation)

RAD51 expression decreased upon exposure to HDACs; tumor weight in vivo lower with combination Rx with

chemotherapy

• Suggestive of a synergistic approach to treat adult sarcomas• Drawback has been longer exposure to HDACi may not be clinically tolerable

Hamlet, V, ii (1600-01)

• Hamlet: Come on, sir.• Laertes: Come, my lord.

[They play and Hamlet scores a hit]• Hamlet: One.• Laertes: No.• Hamlet: Judgment.• Osric: A hit, a very palpable hit.• Laertes: Well, again.• King Claudius: Stay, give me drink. Hamlet, this pearl is thine.

Here's to thy health! Give him the cup.

Question 5

What is the follow up on a promising proapoptotic antibody?

35010 Chawla et al. anti-DR5 mAb phase II (p. 80)

• Phase I data indicated 2 responders with conventional chondrosarcoma and one with synovial sarcoma (SS)

• Phase II 15 mg/kg mAb loading, 10 mg/kg dose q3wk• 14 chondrosarcomas: 0 RECIST PR; 8/14 SD best result;

resection of two patients’ tumors: 50, 60% necrosis

35010 Chawla et al. anti-DR5 mAb phase II

• 1 pt with SS: lung involvement, Rx x 1 → resp distress, Rx with anticoagulation for pulmonary embolus, G5 hemoptysis. Postmortem: necrotic tumor

• Not dissimilar from patients with SS treated with sorafenib at our hospital

• Clearly an issue with further development of drug; anti-DR4? TRAIL/Apo2L ligand itself in development

Two quotations

All’s Well that Ends Well, II, i (1602-03)• Helena: "Oft expectation fails, and most oft there

Where most it promises; and oft it hitsWhere hope is coldest, and despair most fits.”

Romeo and Juliet, V, iii (1594-96, 1st perf. 1662)• Romeo: "O true apothecary!

Thy drugs are quick. Thus with a kiss I die."

Question 6

What remains controversial regarding sarcoma management?

35001 Whelan et al. Rx of Pleo RMS (p.79)

• 17 of 23 physicians queried had responded as to how best to treat 7 cm thigh pleomorphic RMS in adults

• 9 recommended extra staging beyond chest CT• 13 recommended chemotherapy without a

consistent regimen noted • RT suggested by 11• Not a lot of consensus!

Midsummer Night’s Dream, IV, I (1595-1596)

• Hippolyta: I was with Hercules and Cadmus once, When in a wood of Crete they bay'd the bear With hounds of Sparta: never did I hear Such gallant chiding: for, besides the groves, The skies, the fountains, every region near Seem'd all one mutual cry: I never heard So musical a discord, such sweet thunder.

35060 Whelan et al. Three EOI randomized studies (p.84)

• 1067 patients in three studies, MRC/EORTC BO02/80831, BO03/80861 , BO06/80931

• All three used standard arm [Cis 100/m2 + Dox 75 mg/m2] x 6• Experimental arms: (1) + HD MTX, (2) + T10-like, (3) Dose

compressed• Median follow up 9+ years, 533 treated in standard arms• Survival was 56% and 52% at 5 and 10 years respectively. Limb

salvage rate 69%. • No improved survival in the experimental arms

Overall survival data

As discussed in JCO, 9/2008

Jaffe N and Gorlick R, JCO 2008; 26: 4365

A Midsummer Night’s Dream, I, i (1595-96)

• Lysander: Ay me! for aught that I could ever read,Could ever hear by tale or history,The course of true love never did run smooth;But either it was different in blood—

• Hermia: O cross! too high to be enthrall'd to low.• Lysander: Or else misgraffèd in respect of years—• Hermia: O spite! too old to be engag'd to young.• Lysander: Or else it stood upon the choice of friends—• Hermia: O hell! to choose love by another's eyes.

• These data suggest that while active, HD MTX may not add to the dox-cis backbone. Are we selecting the already sensitive tumors?

• Can new data move the field? (Maybe not late on the last day of the meeting.)

Finale

WICHITA, KS, 4 November 2008—In a thrilling conclusion to one of the longest and most anticipated elections in U.S. history, charismatic Democrat Alan Klemke defeated opponent Carl Ferguson

to become the new alderperson for Wichita's 4th District.

KLEMKE WINS!Democrat Alan Klemke Becomes Wichita's 4th District Alderman

Latest Cheney Tape May Contain Evidence Of His Whereabouts

WASHINGTON, 6 November 2008—Reports surfaced Tuesday that the New York–based Fox News Channel has obtained a tape which purportedly features another cryptic video message from U.S. vice president and known extremist Dick Cheney, widely regarded as the most feared man in America.

International Con Man Barack Obama Leaves U.S. With $85 Million In Campaign Fundraising (11 Nov 2008)

Next year is just around the corner

Othello, III, iii (1604)

Othello: Excellent wretch! Perdition catch my soulBut I do love thee! and when I love thee not, Chaos is come again.

London, 2008?

MacBeth, I, i (1605-06, 1st perf. 1611 Globe Theatre)

• 1st Witch: "When shall we three meet againIn thunder, lightning, or in rain?"

Miami, 2009

Sonnet XVIII (1609)

Shall I compare thee to a summer's day? Thou art more lovely and more temperate: Rough winds do shake the darling buds of May, And summer's lease hath all too short a date: Sometime too hot the eye of heaven shines, And often is his gold complexion dimm'd; And every fair from fair sometime declines, By chance or nature's changing course untrimm'd; But thy eternal summer shall not fade Nor lose possession of that fair thou owest; Nor shall Death brag thou wander'st in his shade, When in eternal lines to time thou growest: So long as men can breathe or eyes can see, So long lives this and this gives life to thee.

Also moving from London to Miami…

• The limpid words of England give way to the doggerel of Tin Pan Alley

• The Taming of the Shrew was incorporated into Cole Porter’s Kiss Me, Kate (Book: Samuel and Bella Spewack), opening December 30, 1948

• In one scene, the boss of the mobsters, with a debt to collect from one of the principals, is killed. The mobsters then have no bone to pick with the principal, but don’t leave without singing:

CTOS 2009

Eden Roc HotelNovember 4 – 7, 2009