1) Aggressive fibromatosis is a rare soft tissue tumor that typically affects young adults. Surgery is the main treatment but recurrence is common. 2) New evidence shows systemic therapies like sorafenib, hormonal therapies, and chemotherapy can control the disease. A large trial found sorafenib significantly reduced recurrence compared to placebo. 3) Further research is still needed to determine optimal chemotherapy regimens and biomarkers to predict response to various treatments. "Wait and watch" may be suitable for less aggressive cases. Management of fibromatosis remains challenging due to the lack of high-quality data from India and validated patient-reported outcome measures.

1. Aggressive Fibromatosis (desmoid)
– Recent advances and the
evidence
Dr Sameer Rastogi
Assistant Professor,
Medical Oncology(Sarcoma Clinic)
AIIMS, New Delhi
Email- samdoc_mamc@yahoo.com

2. Why this topic?
• No takers for the disease being extremely
rare 1 in million!
• Happens in young adults and typically
coincides with the time of independent living
• Pain, deformity, contractures in extremity
and rest depends upon sites
• Long term opioid use, isolation, depression,
interruption of education, employment 1
J Clin Oncol 2017; 35: Suppl: 11022.
abstract.

3. Epidemiology of fibromatosis
• Age Group – 15 to 60 years (peak age 30-40
years)
• Female predominance – 2 to 3 folds
• Desmoid type fibromatosis develops in 5 to 30%
of patients of FAP 1,2
• FAP asscociated desmoid accounts for 2-10% of
all Desmoids
1.Desmoid tumors characterization of patients seen at Mayo Clinic
1976-1999. Fam Cancer. 2006;5(2):191-194.
2.A nation-wide study comparing sporadic and familial adenomatous
polyposis-related desmoid-type fibromatoses. Int J Cancer. 2011;129(1):256-261.

4. • With aggressive follow up and in those
receiving prophylactic colectomy, DTF has
been reported to be the most common cause
of death

5. Site Distribution

6. Aggressive fibromatosis and the
evidence
• Molecular Biology
• Pathology and molecular testing relevance
• Treatment options
• Surgery
• Wait and watch
• Hormonal/ tyrosine kinase/ chemotherapy
• IRCH Data

7. Biology and treatment of Aggressive fibromatosis Mayo Clin Proc. n June 2017;92(6):947-964

8. Mayo Clin Proc. n June 2017;92(6):947-964

9. Aggressive fibromatosis and the
evidence
• Molecular Biology
• Pathology and molecular testing relevance
• Treatment options
• Surgery
• Wait and watch
• Hormonal/ tyrosine kinase/ chemotherapy
• IRCH Data

10. Diagnosis
• Histopathology confirmation mandatory by
expert soft tissue pathologist1
• On immunostaining –
• Nuclear accumulation of β catenin (though non
specific)
• 85-90% harbor mutations in β catenin gene
leading to accumulation of β catenin in nucleus.
1. Eur J Cancer 2016; 58: 90–96.

11. β catenin
Courtesy – Dr Rimli/ Dr Adarsh Barwad

12. 8 year old boy progressing to
tam/celecoxib/ surgery
β catenin negative
fibromatosis
Courtesy – Dr Rimli/ Dr Adarsh Barwad

13. Molecular analysis
• Activating mutation in CTNNB1 must be done in all the cases if
there is doubt about the diagnosis or in equivocal cases.
• β catenin and APC mutation are mutually exclusive
• Negative β catenin in desmoid should raise the suspicion of familial
or some other diagnosis
• T41A and S45F are by far the most common mutations in DF
accounting for roughly 50% and 25%, respectively S45P is the third
most common mutation at around 9%
• In 4 independent series S45F has been shown to be independent
factor for the recurrence.
Annals of Oncology 28: 2399–2408, 2017
Am J Pathol 2008; 173: 1518–1527
Br J Cancer 2010; 102: 1032–1036.

14. Aggressive fibromatosis and the
evidence
• Molecular Biology
• Pathology and molecular testing relevance
• Treatment options
• Surgery
• Wait and watch
• Hormonal/ tyrosine kinase/ chemotherapy
• IRCH Data

15. Options in treatment of fibromatosis
• Surgery
• Wait and watch
• Systemic hormonal therapy and NSAIDs
• Tyrosine kinase inhibitors – imatinib,
sorafenib and pazopanib
• Chemotherapy methotrexate, vbl,
doxorubicin

16. Treatment for fibromatosis
• Primary surgery –
Eurpean consensus – EORTC, SPAEN, STBSG Annals of Oncology 28: 2399–2408, 2017
Clinical Cancer Research 2011

17. Why STS paradigm might not fit--
• Margin positivity is of doubtful relevance for
local recurrence1
• 25 to 50% recurrences after first surgery while
90% chances after 2nd surgery
• There is discrepancy between the number of
recurrent surgeries they go ahead but the
amputation that is hardly reported in literature2
Extremity and trunk desmoid tumors: a multifactorial analysis of outcome, Cancer
1999, vol. 86 10. 2045-2052
S. Bonvalot et al. Annals of Oncology, Volume 23, Issue suppl_10, 1 September 2012

18. Wait and Watch
• Spontaneous regression has been reported in
5% of patients in retrospective series
• Probably it is undercalculation
• At that time surgery was done for resectable
fibromatosis while those with multiple
recurrences were kept for watch and see
Br J Surg, 2004 vol. 91 1624-1629

19. • Two centre retrospective data
• Primary end point was cumulative probability
of dropping out from wait and watch policy
J Bone Joint Surg Am. 2014 Apr 16;96(8):631-8

20. J Bone Joint Surg Am. 2014 Apr 16;96(8):631-8

21. If done nothing what will be the
course
J Bone Joint Surg Am. 2014 Apr 16;96(8):631-8

22. Tamoxifen and NSAIDS
• In an analysis (n=40) 100 % expression of
estrogen receptor β1
• NSAIDs act through Wnt pathway
• No clear cut benefit of using the combination or
hormonal agents
• Limited toxicity
• Low cost
• Low response rates
Oncol Res Treat 2015;38:244-248
1. Cancer. 2006 Jan 1;106(1):208-13.

23. Skapek et al. PBC 2013

24. EORTC Guidelines
Eurpean consensus – EORTC, SPAEN, STBSG Annals of Oncology 28: 2399–2408, 2017

25. Imatinib
• Largest data comes from SARC phase 2 trial
• N=51
• Imatinib was used at 300mg twice a day
• RECIST response rate was 6%
Clin Cancer Res. 2010 Oct 1;16(19):4884-91

26. • Double blind phase 3 trial
• n =87
•Randomized to sorafenib (400mg per day or matching
placebo)
Gounder et al. NEJM 2018

27. 2 year PFR- 81% vs 36%

28. Sorafenib for advanced desmoid
tumors
• Objective response rates were 33% vs 20%
(sorafenib arm vs placebo arm)
• In the patients who had response – Median
time to response was 9.6 months

29. Chemotherapy regimen used in
fibromatosis
• Low dose vinblastine and methotrexate – single
phase 2 trial in adults
• Weekly mtx 30mg/m2 and vinblastine 6mg/m2
• N=30 (inoperable recurrent patients)
• PR -40% and Stable disease 60% on treatment
• 4 (13%) patients received less than 15 cycles due
to toxicity
Azarelli ACancer. 2001 Sep 1;92(5):1259-64

30. • N=62
• Methotrexate and vbl –n=21
• Anthracyclines – n=13
• ORR was 21% and PD was 19% and rest SD
• Response rate was higher in anthracyclines as
compared to methotrexate and vbl (54% vs
12%)
• Median PFS was 40 months
Annals of Oncology 23: 182–186, 2012

31. • Randomization between pazopanib 800mg to
methotrexate vinblastine
ASCO 2018 abs

32. Response rates
37% 25%

33. Aggressive fibromatosis and the
evidence
• Molecular Biology
• Pathology and molecular testing relevance
• Treatment options
• Surgery
• Wait and watch
• Hormonal/ tyrosine kinase/ chemotherapy
• IRCH Data

34. Take home message
• Till now no PRO tools validated only progression free
survival or response
• Beta catenin mutations to be considered for difficult
diagnosis and prognosticating
• Wait and watch policy for less aggressive disease
• For aggressive tumors and symptomatic
• Extremity – sorafenib
• Abdomen and head and neck – chemotherapy
• Lot of work – Best chemotherapy options, hormonal
therapy role, pazopanib, biomarkers need to be done
• Data from India except case reports needs to come
soon