Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

P-OGC77 Why curative treatment rates are so low for stage I/II Oesophago-gastric cancer in the West of Scotland? – A five year review

Background Over the last decade, quality performance indicators (QPIs) have been used to drive improvements in cancer care in Scotland. QPI-11 targets curative treatment rates for oesophago-gastric (OG) cancer and this target has been consistently missed. This study aimed to investigate why patients with potentially curable Stage I and II OG cancer did not receive curative treatment. Methods The West of Scotland MCN database was interrogated for patients with newly diagnosed stage I and II OG cancer between January 2015 and December 2019 to identify those patients who did not have curative treatment. Electronic records were then analyzed and the reason for the non curative treatment recorded. Results 260 patients (mean age 78.3 ± 9 years; 114 (43.8%) female) were identified. Median Scottish Index of Multiple Deprivation was 4 (IQR 2-7). There were 159 (61.2%) oesophageal cancers, 196 (75.4%) adenocarcinomas and 174 (66.9%) were Stage II cancers. Formal CPEX fitness was assessed in only 20 patients (7.7%). Reasons for curative treatment not being received were as follows: not clinically fit (n = 216 (83.1%)); patient declined curative treatment (n = 17 (6.5%)); disease progression (n = 16 (6.2%)) and identification of synchronous cancers (n = 9 (3.5%)). Conclusions Lack of fitness for radical treatment is the predominant reason for Stage I and II OG cancer patients in the West of Scotland not being treated with curative intent. This may be related to the previously described “West of Scotland” effect on health comorbidities.

SP5.1.9 Why are curative treatment rates so low for stage I/II Oesophago-gastric cancer in the West of Scotland?

Aims Over the last decade, quality performance indicators (QPIs) have been used to drive improvements in cancer care in Scotland. QPI-11 targets curative treatment rates for oesophago-gastric (OG) cancer and this target has been consistently missed. This study aimed to investigate why patients with potentially curable Stage I and II OG cancer did not receive curative treatment. Methods The West of Scotland MCN database was interrogated for patients with newly diagnosed stage I and II OG cancer between January 2018 and December 2019 to identify those patients who did not have curative treatment. Electronic records were then analysed. Results 81 patients (mean age of 79.3 ± 8.9 years; 41 (50.6%) female) were identified. Median Scottish Index of Multiple Deprivation was 3 (IQR 1-7). There were 46 (56.8%) oesophageal cancers, 49 (60.5%) adenocarcinomas and 63 (77.8%) were Stage II cancers. Formal CPEX fitness was assessed in only 6 patients (7.4%). Reasons for curative treatment not being received were as follows: not clinically fit (n = 69 (85.2%)); patient declined curative treatment (n = 7 (8.6%)); disease progression (n = 3 (3.7%)) and identification of synchronous cancers (n = 2 (2.5%)). 61 patients (75.3%) are deceased at the time of analysis, with a median time from MDT discussion to death of 6 (IQR 2-11.5) months. Conclusions Lack of fitness for radical treatment is the predominant reason for Stage I and II OG cancer patients in the West of Scotland not being treated with curative intent. This may be related to the previously described “West of Scotland” effect on health comorbidities.

973 Why Are Curative Treatment Rates So Low for Stage I/II Oesophago-Gastric Cancer in The West of Scotland?

Aim Over the last decade, quality performance indicators (QPIs) have been used to drive improvements in cancer care in Scotland. QPI-11 targets curative treatment rates for oesophago-gastric (OG) cancer and this target has been consistently missed. This study aimed to investigate why patients with potentially curable Stage I and II OG cancer did not receive curative treatment in the West of Scotland. Method The West of Scotland MCN database was interrogated for patients with newly diagnosed stage I and II OG cancer between January 2018 and December 2019 to identify those patients who did not have curative treatment. Electronic records were then analysed. Results 81 patients (mean age of 79.3 ± 8.9 years; 41 (50.6%) female) were identified. Median Scottish Index of Multiple Deprivation was 3 (IQR 1-7). There were 46 (56.8%) oesophageal cancers, 49 (60.5%) adenocarcinomas and 63 (77.8%) were Stage II cancers. Formal CPEX fitness was assessed in only 6 patients (7.4%). Reasons for curative treatment not being received were as follows: not clinically fit (n = 69 (85.2%)); patient declined curative treatment (n = 7 (8.6%)); disease progression (n = 3 (3.7%)) and identification of synchronous cancers (n = 2 (2.5%)). 61 patients (75.3%) are deceased at the time of analysis, with a median time from MDT discussion to death of 6 (IQR 2-11.5) months. Conclusions Lack of fitness for radical treatment is the predominant reason for Stage I and II OG cancer patients in the West of Scotland not being treated with curative intent. This may be related to the previously described “West of Scotland” effect on health comorbidities.

Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers

Along with early-onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown. We screened 71 patients with MPC of the stomach, colorectal, and endometrium, sequencing 65 cancer predisposition genes. A subset of 19 patients with early-onset MPC of stomach and colorectum were further evaluated for variants in cancer related genes using both normal and tumor whole exome sequencing. Among 71 patients with MPCs, variants classified to be pathogenic were observed in 15 (21.1%) patients and affected Lynch Syndrome (LS) genes: MLH1 (n = 10), MSH6 (n = 2), PMS2 (n = 2), and MSH2 (n = 1). All carriers had tumors with high microsatellite instability and 13 of them (86.7%) were early-onset, consistent with LS. In 19 patients with early-onset MPCs, loss of function (LoF) variants in RECQL5 were more prevalent in non-LS MPC than in matched sporadic cancer patients (OR = 31.6, 2.73–1700.6, p = 0.001). Additionally, there were high-confidence LoF variants at FANCG and CASP8 in two patients accompanied by somatic loss of heterozygosity in tumor, respectively. The results suggest that genetic screening should be considered for synchronous cancers and metachronous MPCs of the LS tumor spectrum, particularly in early-onset. Susceptibility variants in non-LS genes for MPC patients may exist, but evidence for their role is more elusive than for LS patients.

Somatic Tumor Profile Analysis in a Patient with Germline PMS2 Mutation and Synchronous Ovarian and Uterine Carcinomas

Lynch syndrome patients with synchronous endometrial and ovarian cancer (SEOC) are rare. When these cases occur, they are most often endometrioid histology and early grade. Early-grade tumors are not often sent for somatic tumor profiling. We present a 39 year old SEOC patient with germline PMS2 Lynch syndrome and clinical tumor analysis leading to insight regarding the origin and cause of these tumors, with potential therapy options. PMS2-related SEOC is less common due to lower risks for these cancers associated with germline PMS2 mutation compared to other Lynch genes. While synchronous cancers are not common, they are more likely to occur with Lynch syndrome. Tumor profiling with next-generation sequencing of 648 genes identified sixteen shared somatic actionable and biologically relevant mutations. This case is a rare example of a patient with PMS2 germline Lynch syndrome with shared somatic variants that demonstrate clonality of the two tumors arising from one common site.

High-Tech radiotherapy for primary prostate cancers and synchronous other tumor in elderly

Aims: To report feasibility and efficacy of high-tech Radiotherapy (RT) for the treatment of synchronous Multiple Primary Malignancies (sMPM) for elderly patients with primary Prostate Cancer (PC). Methods: Two elderly patients with PC and synchronous Anal Cancer (AC) and sacrum chordoma, respectively, were described. The first one was treated with radical radio-chemotherapy. A total dose of 70 Gy / 65.5 Gy (28 fractions) was prescribed to prostate/ seminal vesicles, and concomitantly, 56 Gy / 50.4 Gy / 45 Gy were prescribed to tumor, anal canal/mesorectum/pelvic nodes, and inguinal nodes, respectively. For the second case, after resection of chordoma, adjuvant and prostate radical RT (65.5 Gy / 70 Gy) in 28 fractions were used. In both cases, Volumetric-Arc RT was performed. Results: Patients completed the planned treatment without severe toxicities. After a median follow-up of 12 months, no sign of PC and a controlled/reduction of chordoma/AC were observed. Conclusion: High-tech RT is safe and effective for sMPM elderly patients. Keywords: Synchronous cancers; Elderly; Treatment; Radiotherapy; Multidisciplinary evaluation.

Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers

BackgroundAlong with early onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown.MethodsWe screened 71 patients with MPC of the stomach, colorectal, and endometrium, sequencing 65 cancer predisposition genes. A subset of 19 patients with early onset MPC of stomach and colorectum were further evaluated for at DNA repair and cancer related genes using both normal (germline) and tumor (somatic) whole exome sequencing.ResultsAmong 71 patients with MPCs, variants predicted to be pathogenic were observed in 15 (21.1%) patients and affected Lynch Syndrome (LS) genes: MLH1 (n=10), MSH6 (n=2), PMS2 (n=2), and MSH2 (n=1). All carriers had tumors with high microsatellite instability and 13 of them (86.7%) were early-onset, consistent with LS. In 19 patients with early-onset MPCs, loss of function (LoF) variants in RECQL5, including a rare East-Asian specific variant, were more prevalent in non-LS MPC than in matched sporadic cancer patients (OR=31.6, p=0.001). Additional evaluation of bi-allelic alterations in the tumor correctly identified LS genes in LS patients and candidates genes in non-LS patients including high-confidence LoF variants in 2 patients, FANCG (c.307+1G>C) and CASP8 (p.R221Sfs*17) both accompanied by somatic loss of heterozygosity in a gastric and a colorectal tumor, respectively.ConclusionsThe results suggest that genetic screening should be considered for synchronous cancers and metachronous MPCs of the LS tumor spectrum, particularly in early-onset patients. Susceptibility variants in non-LS genes for MPC patients may exist, but evidence for their role is more elusive than for LS patients.

Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency

Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.