Medullary Thyroid Cancer. Caroline S. Kim, MD Perelman School of Medicine at the University of Pennsylvania February 13, 2016

Transcription

1 Medullary Thyroid Cancer Caroline S. Kim, MD Perelman School of Medicine at the University of Pennsylvania February 13, 2016

2 I have no disclosures

3 30 minutes on Medullary Thyroid Cancer (MTC) Classification RET genotype-phenotype Pre-operative Testing Surveillance Metastasis

4 Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma -? Add in Expert Opinion slide

5 Background MTC MTC rare, present in % thyroid nodules C-cells 2-4% of the thyroid gland No gender bias ,500 cases US; 12,500 worldwide

6 Hereditary MTC Hereditary: MEN2: 25% MEN 2A: Classical MEN2A (MTC, pheochromocytoma, HPTH) MEN2a w/hirschprung s (exon 10, 620 mutation) MEN2A with cutaneous lichen amyloidosis (Upper back), mostly codon 634 FMTC (familial medullary thyroid carcinoma) **now a variant of MEN2A MEN 2B (pheo, gangilioneuromatosis, characteristic phenotype) no hyperparathyroidism

7 MEN2B Typically de novo (>75%) Surgery is therapeutic vs prophylactic; usually presents clinically

8 Driver Mutations Mutations (germline or sporadic) confer growth advantage or a failure of cells to die MEN2A and 2B: activating Sporadic MTC: activating RET (most common 918) Activating RAS Chr 1p and 22q deletions in MTC

9 Molecular Drivers of MTC BRAF is not a driver RET/RAS Ras ->BRAF=>MEK=>ERK MEN2A, FMTC (RET) MEN2b: RAS

10 RAS-cont d HRAS codon 61, most common MTC NRAS codon 61, non-medullary thyroid cancer

11 RET (rearranged in transformation) Constitutively activated mutation Same RET in PTC (in fusion-ionizing radiation) Less expression in follicular thyroid cells

12 RET mutations Driver mutation 25% hereditary MTC-MEN2A or MEN2B -almost all exons 10 and 11 rarely 5,8,13,14,15 and 16-95% MEN2B RET M918T or RET A833F (maybe less aggressive)

13 RET Proto-Oncogene in MTC RET transmembrane kinase Signal pathways RET to Ras to Pi3K or BRAF RET activates cell growth (proliferation); also? Role in avoiding apoptosis

14 RET gene DNA mrna mrna Intron Exon 10 Intron Exon 11 Intron - - Exon 16 ATG ACG RET-wild type RET-mutant Methionine to Threonine ATG -> ACG point mutation

15 Sporadic MTC 75% sporadic 1-7% sporadic MTC have MEN2 50% somatic RET mutations RET codon M918T-aggressive somatic RAS (HRAS/NRAS, not KRAS) Mutually exclusive 75% sporadic 4 th an 6 th decade; equal M;F 70% palpable nodule will have cervical involvement and 10% will have distant metastasis

16 Sporadic 918 or RAS mutation Not considered standard of practice to analyze for somatic RET or RAS mutations in sporadic MTC Codon 918 with poorer prognosis

17 Table 4. Relationship of Common RET Mutations to Risk of Aggressive MTC in MEN2A and MEN2B, and to the Incidence of PHEO, HPTH, CLA, and HD in MEN2A

18 Presentation Thyroid nodule Most c-cells migrate in embryonic development, reside in entral upper portion of thyroid lobes Hereditary MTC, distribution in upper lobes Sporadic MTC: can be different locations of the thyroid ** add image**

19 Risk Categories: NEW Classification A (lowest) and D (highest) A & B Moderate All others C High Codon 634 D Highest Codon 918

20 Germline genetic testing 1 st degree relatives with proven hereditary MTC Features MEN2b, cutaneous lichen amyloidosis (634) MEN2B Sequencing: analysis exons 10 (609, 611, 618, 620) and exon 11 (634) and mutations in exons 8, 13, 14,15 and % of all mutations will be found this approach Entire GENE sequencing kindreds no identifiable mutation

21 Tumor Markers Calcitonin: significant elevation >100 g/ml most likely MTC (other cells and HASH) Carcinoembryonic antigen (CEA) Marker of tumor progression No real provocative testing (calcium or pentagastrin) Response to TKI see decrease in calcitonin and CEA

22 Pre-op staging Recommendation 22 (Grade C) If CTN >500 pg/ml, evaluate for metastases CT neck/chest, liver CT/MRI Central neck (Rec 25) Yes even if no preoperative findings So total thyroidectomy +central LN dissection

23 Lateral neck dissection Elective (II-V) May consider depending on CTN level! Therapeutic yes Distant disease: balance the surgical approach

24 Recommendation 48: Postop Calcitnoin <150 pg/ml unlikely to have pimage-positive disease, serial labs US q6 month/clinical If >150 pg/ml, metastatic survey Neck recurrence

25 Rec 49: postop calcitonin >150 pg/ml, image Neck recurrence Rec 51 Compartment dissection of image-positive or biopsy-positive disease in central (level VI) or lateral (Levels II-V) Resection of only grossly metasatic LN or other imited porcedures Grade C recommendation

26 Recommendation 30: Distant metastasis -less aggressive surgery NEED the imaging before going for surgery MUST have calcitonin/cea PRIOR to surgery

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28 Recurrence of MTC Recurrence definition Control/curative/palliative Non-medical symptom treatment Extent of disease/restaging Dynamic Staging

29 Where is the recurrence Lymph nodes ½ (cervical/mediastinum/other) ½ metastatic (liver/lung/bone) Burden of disease associated with symptom Bony metastases/bone pain Diarrhea (common w/mtc) Fatigue SOB Flushing/anorexia

30 Doubling Times Calcitonin ** Put image in**

31 Only local regional disease If curative option, consider surgery (first surgery is most important) XRT can be curative but likely recurrence Fail or not options, systemic therapy can be used for local disease If calcitonin not rising, consider observation

32 Metastatic MTC Debulking may be useful Calcitonin is a good tumor marker; volume correlates with calcitonin and CEA levels

33 Disconnect calcitonin and disease As disease progresses, may not be able to use as well? What is a good biomarker CEA is a better biomarker

34 Distant Metastasis Additional mutations Hormonally active? Location of metastases Common: mediastinum, lung, liver and bone If calcitonin <150 pg/ml : unlikely to find >1000 pg/ml should find

35 Imaging Liver: MRI Neck/Chest (Us/Chest) Bone: bone scan is preferred PET: less helpful

36 Management Metastases Debulking XRT Hepatic metastases: chemoembolization, Systemic therapy: TKIs

37 Interesting-? prognosis? Somatic RET mutation worse outcome Ellisei, R (jcem 2007; ) However RAS mutation does not (Ciampi et al; 2013 Thyroid 23:50) Lack of RET mutation-higher disease free Controversy: MDACC shows no difference in survival with mutation, RET may have worse survival No mutation, is assoc with worse prognosis MDACC shows RAS does not appear to effect prognosis May depend on presentation/referral bias?

38 Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial; Wells,S et al. J Clin Oncol 2012: 30 ( ) Partial vs complete responses to TKI Vandetanib, carbozatinib: FDA approved Vandetanib: RET, VEGFR, EGFR Approved for unresectable locally advanced or metastatic disease Phase 3 PFS (30 vs 19 months Overall survival? Terminated early Side effect profile (12% d/c compared with 3% placebo (Diarrhea 16%, palmar-plantar erythrodysethesia 13%, HTN 8%, prolonged QT, HA, nausea, leukopenia)

39 Cabozantinib in Progressive Medullary Thyroid Cancer Rossella Elisei, Martin J. Schlumberger, Stefan P. Mu ller, Patrick Scho ffski, Marcia S. Brose, Manisha H. Shah, Lisa Licitra, Barbara Jarzab, Viktor Medvedev, Michael C. Kreissl, Bruno Niederle, Ezra E.W. Cohen,Lori J. Wirth, Haythem Ali, Colin Hessel, Yifah Yaron, Douglas Ball, Barry Cabozantinib (XL 184) 11.2 vs 4 month PFS Can decrease Calcitonin and CEA level

40 Cabozantinib cohort RAS mutation analyzed in the RET negative ccohort Of 85 patients/16 RAS mutation (19%) RAS mutation positive did respond (13 treated/3 placebo) Median PFS 47 wks vs 8 wks (but only 3 placebo)

41 Carbozantinib (JCO trial) 2:1 randomization Waterfall plot, almost everyone had tumor shrinkage Progression free survival (PFS), compared with placebo arms Median 4 months PFS (aggressive population) Correlation CEA/Calcitonin and tumor size Biochemical correlate Toxicity: oral agents shorter ½ life

42 Molecular parameters RET subtype No difference hereditary vs sporadic RET mutations had advantage on response to carbozantinib RET negative people not as much (small n though) RET M918T more benefit Even RET wild-type will respond

43 RET negative and TKIs YES-treat them with vandetanib/carbozatinib RET wild-type can benefit? Multifactorial kinases (VEGFR) that are affected

44 Starting Therapy-Review who to Consider? General performance Symptomatic-what are we looking for? DISEASE PROGRESSION Recist? XRT CEA (maybe) Calcitonin (no)

45 Hormonal Manifestations of MTC Calcitonin: octreotide to control diarrhea ACTH cushing s (CRH) (adrenalectomy, metrapyrone, ketoconazole), AVP hyponatremia (fluid restriction, V2 antagonist) Diarrhea (16%); palmar-plantar (13%); HTN (8%)

46 Conclusions MTC is rare Genotype-Phenotype Correlation Revised classification -early detection/management in children Utility of calcitonin/cea follow-up Timing of intervention for Recurrence TKIs for metastatic disease