Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance

Here we report a kindred formed by 16 individuals with a very severe FAP phenotype. A two-base deletion mutation: c.4393_4394 del AG in APC gene and a consequent premature stop codon was detected. DTs were diagnosed in 6 individuals, ranging from 2 to 25 years of age. The causes of death were diverse: gastric cancer, rectal cancer and desmoid tumor. The already described genotype-phenotype correlation has proved its worth in this family, as clinical features reflect the mutation location at 3′ end of APC gene. The inheritable and lethal nature of the disease needs a tailored follow up approach in order to reduce mortality, optimize local tumor control, and preserve patients’ quality of life.

Aggressive fibromatosis requires coordinated multidisciplinary care to manage. This first report explores the role of Irreversible Electroporation (IRE) in controlling the disease when conventional options are not available. A retrospective evaluation of a single center experience from 05/2012 to 08/2017 revealed 6 patients with biopsy-proven aggressive fibromatosis referred to Interventional Radiology for IRE. Three chest wall tumors, 1 thigh tumor, 1 popliteal tumor, and 3 calf tumors (total of 8 tumors) were treated with IRE (NanoKnife System, AngioDynamics). A total of 10 procedures were performed as 2 lesions were managed in stages due to size. All 8 tumors (100%) achieved a modified Choi PR (7 by tumor density, 1 by size) at a mean follow up of 124 days post-IRE, while none met criteria for RECIST1.1 PR. Five out of 8 eventually met criteria for RECIST1.1 PD with a mean time to progression (TTP) of 335 days post IRE. Four of 6 patients required additional therapy (chemotherapy or another systemic agent) after IRE due to disease progression, with a mean of 520 days until the next treatment. IRE can provide local control of aggressive fibromatosis, though a high rate of recurrence can be expected. Modified Choi criteria may be a more accurate reflection of early treatment response than RECIST1.1 as it captures changes of density when size does not reflect response.

Notch signaling can be deregulated in human cancer. AL101 (formerly BMS-906024), a gamma secretase inhibitor that potently inhibits all Notch receptors, was evaluated. The primary objective was safety and tolerability of multiple IV doses of AL101 and to establish a RP2D. Pts with advanced tumors refractory to standard therapies were included. Primary and secondary endpoints included safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Cohorts were administered escalating doses of AL101 IV weekly (QW) or q 2 weeks (Q2W) using a 3+3 design, with expansion at the MTD in TNBC, NSCLC, and selected other tumors with reported Notch activation. There were dose related increases in exposures over 0.3 to 8.4 mg, and the mean plasma half-life following 4 doses QW was 67 – 148 hours, supporting QW dosing. AL101 at the RP2D was generally well-tolerated and demonstrated sustained Notch inhibition as well as clinical activity across different tumor types. Future trials will evaluate AL101 in tumors with Notch activating mutations.

Differential response to tamoxifen observed in patients (pts) with hormone receptor-positive cancer may be due to variations in tamoxifen metabolism from CYP2D6 genetic polymorphisms that limit exposure to the active metabolite, z-endoxifen (Z). We conducted a phase 1 clinical trial (3+3 design) with estrogen receptor imaging to determine the safety, MTD, and pharmacokinetics (PK) of oral Z. Adults with refractory gynecologic tumors, hormone-positive breast or other solid tumors, or desmoid tumors were eligible with ECOG performance status of 0-2 and adequate organ functions. Z was administered at 20, 40, 60, 100, 140, 200, 280, and 360 mg q day on a 28-day cycle. Estrogen receptor imaging with 16 alpha-[18F]-fluoro-17 beta-estradiol (FES)-PET was performed before dosing and, if positive, repeated during C1W1. We established a targeted maximum dose of 360 mg/day Z and evidence of antitumor activity was observed. Oral Z administration produces Z plasma exposures well above those obtained after therapeutic doses of tamoxifen.

DESMOPAZ is a multicenter non-comparative randomized phase II trial based on a two-stage optimal Simon’s design assessing safety and efficacy of PZ in DT adult patients (pts). All pts had to have documented progressive disease (PD) according to RECIST 1.1 based on two imaging within a 6-months interval. Pts were randomly assigned to receive PZ 800 mg/day orally continuously, or M (30 mg/m^2) + V (5mg/m^2) intravenously once a week for 6 months and then every 15 days for 6 months. Treatment was administered until PD (cross-over then permitted), unacceptable toxicity, and for a maximum of 1 year. The primary endpoint was 6-month non-PD rate according to RECIST 1.1. Accrual started in September 2012 in 12 centers of the French Sarcoma Group. As of December 2017, 72 pts (26 males, 46 females) were included: 48 in PZ-arm (46 assessable) and 24 in MV-arm (20 assessable). After central pathological and radiological review, 38 assessable pts (82.6%) in PZ-arm had tumor shrinkage, resulting in PR in 17 (37%) and SD in 21 (45.7%). In MV-arm, 11 assessable pts (55%) has tumor shrinkage resulting in PR in 5 (25%) and SD in 6 (30%). The 6-month non-PD rate was 86% (95%CI = 72.1-94.7) in PZ-arm (37/43) and 50% (95%CI = 27.2-72.8) in MV-arm (10/20). The primary endpoint of the DESMOPAZ study was reached. PZ has meaningful clinical activity in pts with progressive DT.

We retrospectively reviewed data from all patients treated with low-dose methotrexate(MTX) + vinca alkaloids for FAP-associated DTs in 5 reference centres and cases included into the National rare cancer network were also reviewed and included if sufficiently informative for the study purposes. Radiological responses were assessed using both RECIST and CHOI criteria. We identified 28 patients treated with MTX + vinca alkaloids. All patients had progressive disease before chemotherapy; 17 patients and 9 patients had previously received respectively surgery and/or systemic treatments (i.e. hormone therapy, NSAIDs). Chemotherapy was administered for a median duration of 11 months. According to RECIST criteria (CHOI evaluation is ongoing) complete response, partial response, stable disease, and progressive disease were observed in 1, 17, 10, and 0 patients, respectively. The median progression-free survival (PFS) was 78 months; it was 124 months in responding patients. After chemotherapy withdrawal, MTX + vinca alkaloids rechallenge was offered to 11 patients with progressive disease. In these patients, we obtained a control rate of 100%, resulting in a median second PFS of 64 months. To the best of our knowledge, this is the largest series on the activity of low dose chemotherapy in FAP-related DTs. Our data suggest a tremendous activity of low dose chemotherapy in this very rare subset of patients.