Abstract 1292: Does metastatectomy (M) facilitate cure (Cu) by restoring immunity:tumor remnant (TR) equilibrium (Eq)
Authors: Mazahreh Farah , Chen Zhongning , Safar A Mazin 
Published: June 2022

Metastatic cancer (C) is incurable save for solitary/oligometastatic presentations after curative M, a standard care agnostic to tumor (Tu) biology. Despite complete resection, Cu is achieved only in a minority. Importantly, mechanistic understanding of the above is lacking. Immune checkpoint inhibitor (ICI) monotherapy has produced unprecedented, durable control suggestive of Cu even in bulky Cs. Several insights, including donor-derived Cs in solid organ transplant recipients decades after Cu of donors’ Cs, the notion that Natural Killer (NK) cell action is governed by a ratio to its target cells (given the finite perforin/granzyme B), & Tu Infiltrating Lymphocytes experience all suggest to us that ICI-induced Cu might emerge if Eq is restored between immunity (T-/NK cells) & minimal TR. Such drastic C control requires truncal immunogenic mutation(s), an inducible cell death machinery in C cells & functional immunity, collectively termed here as immune-prone (IP) Cs. We hypothesized that M results in Cu ONLY in IP Cs by debulking (DB) Tu load to a TR, restoring Eq.

We retrieved the progression-free survival plateau (PFS-p), a Cu surrogate, from series reporting on &gt;40 patients in multiple Cs/variable IP strata (reflected by mutation burden). We juxtaposed the PFS-p for ICI monotherapy along curative M & provided the mutational landscape from the literature. PFS-p for ICI & M seem comparable & may be superior in the most IP C (melanoma) since ICI has dual impact; DBs & enhances immunity.

Our aim was to stimulate discussion on the Cu mechanism seen after M, & we suggest, though can’t prove, that such Cu represents an immune phenomenon, therefore applicable only to IP Cs. DB an IP C to a TR may be a prerequisite to restoring immune control, clinically appraised as Cu. Confirmation of IP (e.g. exomic C sequencing to detect truncal mutations), enables limiting M to IP Cs [rationally using neo-/adjuvant ICI] or even considering ICI as the sole DB intervention replacing M.

Histology Intervention 1st Author Year Published # of pts PFS-p % p# M^ Burden* ** % &gt;10 M/Mb~ Melanoma ICI monotherapy Hamid 2017 151 41 0.018 Median: 276Max: 1000+ 55% Metastatectomy Svedman 2016 64 23 NSCLC ICI monotherapy Garon 2015 495 31 0.142 Median: 220Max: 1000+ 50% Metastatectomy Ashworth 2014 757 27 H&N ICI monotherapy Mehra 2018 192 20 0.001 Median: 105Max: 750 25% Metastatectomy Kanzaki 2019 134 36.5 Urothelial ICI monotherapy Motzer 2015 168 24 0.827 Median: 163Max: 755 15% Metastatectomy Lehman 2009 44 21 RCC ICI monotherapy Motzer 2015 821 23 0.360 Median: 63Max: 490 5% *: from Castle et al (https://www.frontiersin.org/articles/10.3389/fimmu.2019.01856/full). Median # of non-synonymous mutations/tumor **: from Alexandrov, et al. Nature 500, 415–421 (2013). https://doi.org/10.1038/nature12477 ^ Mutation~ Mutation/Mega Base of DNA# P value (Chi squared)

Citation Format: Farah Mazahreh, Zhongning Chen, A Mazin Safar. Does metastatectomy (M) facilitate cure (Cu) by restoring immunity:tumor remnant (TR) equilibrium (Eq) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1292.