MTC and MEN2: Past, Present, and Future

Transcription

1 MTC and MEN2: Past, Present, and Future Steven G. Waguespack, MD, FACE Professor Dept. of Endocrine Neoplasia and Hormonal Disorders Department of Pediatrics-Patient Care University of Texas M.D. Anderson Cancer Center Houston, Texas, USA Tulsa, Oklahoma

2 Disclosure of Relevant Financial Relationships Steven G. Waguespack, MD Disclosure: Participant in advisory board for Loxo Oncology

3 Learning Bilateral MTC in MEN2 Objectives 1) To define MTC and MEN2 and review their pathophysiology 2) To describe the clinical presentations of MTC and MEN2 3) To discuss management of MTC and MEN2 in the context of guidelines and novel therapeutics

4 Medullary Thyroid Carcinoma First characterized in a solid nonfollicular histologic pattern, the presence of amyloid in the stroma, and a high incidence of lymph node metastases 1-2% of all thyroid cancers cases in the US in 2018 (est.) 3 FNAB Surg. Path Amyloid 1 Hazard et al. J Clin Endocrinol Metab Jan;19(1): Wells et al. ATA revised MTC Guidelines THYROID 2015

5 MTC Trends Incidence of MTC is rising Diagnosis at older age (?role of prophylactic thyroidectomy) Extent of disease remains similar Disease-specific survival has improved over time, esp. those with regional and distant disease Randle et al. Surgery January ; 161(1):

6 MTC: A Tale of Two Types Hereditary Sporadic Autosomal dominant Germline mutations of the RET proto-oncogene (MEN2A/2B) >95% of childhood MTC/25% in adults Multifocal with CCH No germline RET mutation Somatic RET and RAS mutations & unknown causes <5% of childhood MTC/75% in adults Usually unifocal without CCH

7 Medullary Thyroid Carcinoma (MTC) (> 90%) MEN2A Parathyroid Neoplasia (0-20%) Pheochromocytoma (0-50%) Genetic Mutation NH <10% de novo Cadherin-like domains Cysteine-rich region Transmembrane region Intracellular tyrosine kinase COOH RET tyrosine kinase receptor

8 MEN2A Variants +Cutaneous Lichen Amyloidosis +Hirschsprung Disease Familial MTC MTC only Codon 634 Mutations Exon 10 Mutations (codon 620) ATA-MOD Mutations

9 Medullary Thyroid Carcinoma (MTC) (100%) MEN2B Phenotype (100%) MEN2B Pheochromocytoma (~50%) Genetic Mutation NH >90% de novo Cadherin-like domains Cysteine-rich region Transmembrane region Intracellular tyrosine kinase COOH RET tyrosine kinase receptor

10 MEN2B Phenotype Megacolon Thickened lips and mucosal neuromas Thickened Lips Arachnodactyly and Marfanoid body habitus Pictures from SGW personal collection Thickened corneal nerves Failure to produce tears* Eyelid eversion Constipation and feeding difficulties* Pes cavus SCFE *earliest clinical manifestations; Brauckhoff et al. Surgery 2008;144:

11 Castinetti et al. Endocr Relat Cancer MEN2B Phenotype a b e h c f h d g

12 Somatic Driver Mutations HRAS 10% 40% Unknown in Sporadic MTC KRAS 5% RET 10% Current guidelines do not 45% 70% address intervention M918T based on somatic mutations 2% 1% 6% 4% 3% Mutation Frequency in RET Positive MTC Codon 918 Codon 634 Other Cys deletion Codon 883 Codon 630 Cys spacing Codon 618 Codon 620 Codon 611

13 Survival (%) MTC survival Overall survival better in hereditary MTC Cupusti et al. Ann Surg, 246, , 2007 Years from diagnosis Localized Regional Distant Roman et al., Cancer, 2006

14 Calcitonin and CEA Sensitive tumor markers check fasting and before CT contrast <1% of MTC are non-secretory for CTN 1 Rapid doubling time=worse prognosis 2 CEA trend appears to have a higher predictive value 1 Frank-Raue et al. Thyroid, 2013 Mar;23(3):

15 Calcitonin and CEA Doubling Time

16 MTC Liquid Biopsy: Circulating Cell-Free DNA RET M918T RET M918T RET M918T CTN Doubling time RET M918T RET M918T RET M918T Adapted from Polivka et al, 2015 Expert Rev. Mol. Diagn. 15:1631 Cell-Free DNA (cfdna) RET M918T Better prognostic prediction with a single blood sampling cfdna

17 1 Medullary Thyroid Cancer Hereditary MTC Most often spreads via lymphatic channels 82% with LN mets if tumor 1cm 1 Hematogenous spread to lungs, liver, bone

18 Thyroid Nodule(s)

19 Bulky Neck Disease Tracheal Deviation MTC LN

20 Mediastinal & Intrathoracic LAD Subcarinal and Hilar LAD Tracheal Compression

21 Bone Metastases Spinal Met with Cord Compression Diffuse Bony Metastases 19% of patients Spine (92%) & pelvis (69%) Skeletal-related events common Xu et al. JCEM 2016

22 Liver Metastases 3-Phase CT or MRI

23 Other Symptoms & Clinical Presentations Diarrhea Does not always correlate with CTN levels Other potential secretagogues: CGRP, prostaglandins, 5- hydroxytryptamine, VIP Flushing Cushing Syndrome Ectopic ACTH secretion MEN2 phenotype or positive genetic test MTC Adrenal hyperplasia

24 Guidelines for Care NCCN Guidelines

25 DIAGNOSIS--FNA FNAB MTC Dx may be missed Most FNAs still likely to lead to surgery Afirma MTC classifier 1 Sens 97.9%, Spec 99.8%, PPV 97.9%, NPV 99.8% Amyloid FNA findings that are inconclusive or suggestive of MTC should have calcitonin measured in the FNA washout fluid and IHC staining of the FNA sample to detect the presence of markers such as Ctn, chromogranin, & CEA and the absence of Tg. 2 1 Kloos et al. THYROID

26 DIAGNOSIS-CALCITONIN Sensitivity 100%, specificity 95.3%, PPV 15.4%, NPV 100% 1 MTC identified via CTN screening in 0.4% of patients with nodular thyroid disease 2 False positive CTN elevations CKD, autoimmune thyroiditis, PHPT, other NETs 1 Hasselgren M et al. Head Neck, 32(5):612-8, Elisei R et al. JCEM, 89:163-68, 2004.

27 DIAGNOSIS-CALCITONIN Realizing that opinions of experts vary regarding the usefulness of measuring serum Ctn levels in patients with nodular goiters, the Task Force recommends that physicians decide whether the technique is useful in the management of patients in their clinic.

28 General Approach to MTC Surgery (total thyroidectomy + lymph node dissection) No RAI; Keep TSH normal Genetic Testing Screening for other MEN2 Manifestations Long-term monitoring with blood tests (calcitonin, CEA) and imaging studies (neck US, CT, etc.)

29 Initial Evaluation

30 Wells et al. ATA revised MTC Guidelines THYROID 2015 Surgical Therapy Total thyroidectomy & Central neck dissection (Levels VI- superior VII) Lateral neck dissection (Levels II- V) depending on clinical data* *Lateral neck dissection if imaging-positive disease; in imaging negative disease, lateral neck dissection may be selectively considered based upon CTN levels (No consensus!)

31 Evaluation of Persistently Elevated Calcitonin Neck US/CT Chest CT Liver (abd) MRI or 3phase CT Bone Scan/MRI axial skeleton/pelvis FDG PET/CT less sensitive and of lower prognostic value Giraudet et al. JCEM, 2007, 92(11):

32 68 Gallium Dotatate PET/CT Improved detection rate compared with 111 In-octreotide SPECT/CT and conventional imaging Yamaga et al. Eur J Nucl Med Mol Imaging Sep; 44(10):

33 Treating progressive or symptomatic disease Medical Therapy Cytotoxic Chemotherapy Oral Tyrosine Kinase Inhibitors Vandetanib (approved 2011) Cabozantinib (approved 2012) Clinical trials Symptomatic treatment Palliative radiation Anti-diarrheal medications Pain medications Bone metastases: zoledronic acid,

34 Vandetanib AKAP9/BRAF AKAP9/BRAF AGK/BRAF TERT Pax8/PPARγ Drug IC 50 (nm) EGFR Differentiation, Proliferation, & Survival RET VEGFR 1 VEGFR 2 VEGFR 3

35 Cabozantanib AKAP9/BRAF AKAP9/BRAF AGK/BRAF TERT Pax8/PPARγ Drug IC 50 (nm) Differentiation, Proliferation, & Survival Cabozantinib MET RET VEGFR1 VEGFR2 VEGFR3

36 Inclusion Criteria Cross-over at Progression Median PFS (months) Differences in the Phase III Vandetanib (n=231) Trials for MTC Placebo (n=100) Locally advanced or metastatic AND calcitonin 500 No requirement for progression Not reached (est. 30.5) Allowed Cabozantinib (n=219) Placebo (n=111) Documented RECIST progression within 14 months of enrollment Not allowed year PFS 83% 63% 47% 7% HR (95% CI) 0.35 (0.24, 0.53) 0.28 (0.19, 0.40) ORR 45% 13%* 28% 0% Survival NA NA 27 mo 21 mo

37 Other TKIs studied in MTC

38 The Hope of Targeted Therapy Oct 26, 2007 Vandetanib April 18, 2008 A=18.5mm A=13.5mm B=16mm B=11mm Calcitonin 7662 pg/ml Calcitonin 3404 pg/ml Bone and liver progression in April 2009

39 Unresolved Issues When to start therapy Incomplete responses/ Drug resistance Role RET vs. other targets Survival benefit largely unproven Drug side effects and QoL Role of intermittent therapy Neoadjuvant/adjuvant therapy

40 clinicaltrials.gov; accessed November 2017 Current Clinical Trials Cabozaninib Vandetanib Lutetium-177 Octreotate, 111In- CP04, 177Lu-PP- F11N Recombinant Saccharomyces cerevisiae-cea Nintedanib LOXO-292, BLU- 667 Regorafenib Sulfatinib Rovalpituzumab Pembrolizumab Anlotinib

41 Differentiation, Proliferation, & Survival RET Inhibitors AKAP9/BRAF AKAP9/BRAF AGK/BRAF TERT Pax8/PPARγ

42 Selective RET Inhibitors Subbiah et al., Cancer Discov 2018

43 Response to Selective RET Inhibition BLU patients with MTC & 2 with PTC ORR in MTC: 40% (1CR) LOXO patients with MTC & 9 with DTC ORR in MTC: 45% (1CR) Subbiah et al. AACR 2018 Drilon et al. ASCO 2018

44 Response to Selective RET Inhibition BLU patients with MTC & 2 with PTC ORR in MTC: 40% (1CR) Toxicities: elevated LFTs, tumor lysis, fatigue, diarrhea, constipation, HTN, edema, hyponatremia, elevated crt, HA, WBC decreased, cough Most AEs grade 1, no grade 4/5 AEs LOXO patients with MTC & 9 with DTC ORR in MTC: 45% (1CR) Toxicities: elevated LFTs, tumor lysis, fatigue, diarrhea, constipation, dry mouth, vomiting, dyspepsia Most AEs grade 1, no grade 4/5 AEs Subbiah et al. AACR 2018 Drilon et al. ASCO 2018

45 RET-mutated MTC: Response to a selective RET inhibitor 9/18/17 1/10/18

46 MTC & MEN2:A Brief History 1959: Hazard, Hawk & Crile--MTC 1961: Sipple--33yo with MTC, PHEO, & parathyroid hyperplasia 1966: Williams &Pollock-- multiple mucosal neuromata & endocrine tumours 1968: Steiner, Goodman, & Powers-- MEN2

47 MTC & MEN2:A Brief History 1973: Wolfe et al.--c-cell hyperplasia 1975: Chong et al.--men2a (Sipple Syndrome ) & MEN2B 1985: Takahashi et al. RET cloned 1993: Donis-Keller et al. AND Mulligan et al.--men2a & RET 1994: Hofstra et al. AND Carlson et al.-- MEN2B & RET

48 MEN2 Genotype-Phenotype MEN2A RET tyrosine kinase receptor MEN2B Grubbs and Waguespack in Medullary Thyroid Cancer (Wang and Evans, eds.) 2016

49 Adapted from Waguespack et al. Nat Rev Endocrinol Aug Hereditary MTC Theoretical Progression of C- cell disease in a patient with a RET codon 634 mutation Ideal Window for Intervention Machens et al. NEJM 2007

50 Rationale for Early Thyroidectomy ~100% of gene carriers (most mutations) will develop MTC (a potentially lethal malignancy) during their lifetime MTC is incurable once distantly metastatic & rarely curable once metastatic to cervical LNs Early thyroidectomy appears curative In experienced hands, risks of thyroidectomy should be no greater in a child than in an adult

51 Evolution of Early Thyroidectomy 1970s-early 1990s: Pentagastrinstimulated CTN 1990s-2009: Genotype & earliest onset of disease 2009-present: Genotype PLUS clinical data

52 MEN2 Genotype-Phenotype RET tyrosine kinase receptor Grubbs and Waguespack in Medullary Thyroid Cancer (Wang and Evans, eds.) 2016

53 2015 ATA Guidelines- Timing of Surgery ATA-HST (918) TTx by age 1, perhaps sooner ATA-H (634, 883) TTx by age 5 ATA-MOD (all others) TTx depending on elevated basal or stimulated CTN

54 MTC Aggressiveness after Diagnosis: Does Mutation Matter? Probability of survival and distant metastases similar between codon 634 and moderate risk mutations Voss et al. J Clin Endocrinol Metab 102: , 2017

55 What are the downsides of earlier surgery? Most children with MEN2 don t have access to high volume surgeons higher complication rates?worse oncologic outcome Iatrogenic hypothyroidism Early medicalization of an otherwise normal child

56 Calcitonin Levels in MEN2 Direct relationship to tumor burden CCH can cause elevated CTN CTN may be normal with MTC bctn < pg/ml in presymptomatic child not typically associated with N1 disease Machens et al. Ann Surg: 2009; Elisei et al. JCEM: 2012; Rohmer et al. JCEM: 2011

57 Calcitonin Levels in Children N=151 Basuyau et al. Clinical Chemistry 50, No. 10, 2004

58 When Do We bctn < 40 pg/ml Intervene? Surgeon and pediatrician caring for the patient, in consultation with the child s parents, should decide the timing of thyroidectomy. Wells et al. ATA revised MTC Guidelines THYROID 2015 More Studies Required!

59 Unresolved Issues MEN2 genotype-phenotype continues to evolve Over time, earliest age of disease onset among the various RET mutations will start to look more alike The expanding RET landscape Rare RET mutations and RET VUS Need better predictors of who will develop aggressive disease e.g. aggressive MTC in V804M

60 Lifetime Risk MEN2A (0-50%)(codon 634) MEN2B (50% lifetime risk) Adrenergic phenotype MEN2 & PHEO Bilateral in 61-72% 1,2 & synchronous in 82% 1 Median Age of Dx years 1,2 Dx after MTC in 55-60% 1,2 <1% malignant or extra-adrenal 2 Screen starting at age 11 (codons 634, 918) or 16 (other codons) 3 Treatment: Cortical sparing adrenalectomy 2 PHEO on background of adrenal medullary hyperplasia Retroperitoneoscopic Adrenalectomy 1 Thosani et al. JCEM Castinetti et al. Lancet Oncol 2014

61 Schuffenecker et al. JCEM 1998; Guerin et al. Endocr Relat Cancer 2017 Wells et al. ATA revised MTC Guidelines THYROID 2015 Hyperparathyroidism & MEN2A Up to 20% of patients, depending on genotype Codon 634 mutations Presents after MTC Mean age ~40 yrs No malignancies Screen starting at age 11 (codon 634) or 16 (others) Treatment Individualized surgery Previously autotransplanted parathyroid tissue growing in SCM muscle Only remove enlarged, hyperfunctional glands (in contrast with MEN1) No autotransplantation into the neck (similar to MEN1)

62 Summary MTC is a rare neuroendocrine malignancy with both sporadic and familial forms Surgery remains the best option for cure Guidelines are available to guide management Vandetanib and Cabozantinib are approved for the treatment of advanced MTC Novel therapeutics are on the horizon The timing of early thyroidectomy has evolved and incorporates clinical data into decisionmaking

63 Thank You! mdanderson.org