BRAF L597

The BRAF mutation may represent important genetic alteration in a subset of IDC-P, highlighting the role of MAPK signaling pathway in this subtype of PCa. To the best of knowledge, this is the first description of non-V600 BRAF mutation in setting of IDC-P, which may in part explain the aggressive phenotype seen in IDC-P and could also bring more treatment options for PCa patients with IDC-P harboring such mutations.

Furthermore, TP53, LRP1B, STK11, SPTA1and MAGI2 were significantly over-mutated in Class II and III (p<0.06) and SETD2 is over-mutated in Class I (p<0.001), might suggesting relatively poor prognosis in NSCLC patients. Conclusions The characteristics of Chinese NSCLC were further explored, including BRAF mutation types, the incidence of related co-mutations and TMB value, which is helpful to formulate targeted therapy strategies to adapt to different types of BRAF mutation functions according to their genomic and clinical characteristics.

Introduction: Treatment with neoadjuvant nivolumab plus chemotherapy has demonstrated high efficacy in patients with locally advanced non-small-cell lung cancer (NSCLC)... Our data suggest that BRAF pathogenic variants may be a good prognostic factor in locally advance NSCLC patients treated with neoadjuvant chemo-immunotherapy.

MET fusions are a rare, but potentially actionable, genomic alteration. Our study provides a comprehensive characterization of MET fusions in NSCLC, revealing their diverse fusion partners and co-occurring genomic alterations. Further research is warranted to elucidate the clinical implications of MET fusions in the treatment of various types of cancer, including lung cancer.

The study highlights the heterogeneity of patients with BRAF class II and class III regarding histology and co-mutational status, with both classes equally frequent. A more granular investigation of non-V600X alterations and their associated clinical outcomes under different treatment approaches is ongoing.

P1/2, N=37, Terminated, Haihe Biopharma Co., Ltd. | N=150 --> 37 | Trial completion date: Dec 2024 --> Mar 2023 | Recruiting --> Terminated | Trial primary completion date: Dec 2023 --> Mar 2023; Sponsor business decision

Concomitant BRAF L597Q mutation and PPM1D mutation are novel findings. The overall prognosis of this tumor is poor, with tumors located in the brainstem showing worse outcome.

P1/2, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2023 --> Feb 2024 | Trial primary completion date: Feb 2023 --> Feb 2024

Novel BRAF mutations and V600E were frequently detected in thyroid cancer of Libyan patients; this suggests a potential role of these novel mutations in carcinogenesis and in anti-EGFR therapy resistance.

P1/2, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=38 --> 17

Rare BRAF mutations are not anecdotal in the metastatic melanoma population. Although data interpretation must remain careful owing to the limited size of some subsets of patients, non-E/K V600 BRAF mutations seem to confer a high sensitivity to targeted therapy, whereas MAPKis seem less effective in patients with non-V600 BRAF mutations. However, this strategy may be used as an alternative option in the case of immunotherapy failure in the latter population.

Four patients received combined BRAF/MEK inhibitors, two patients BRAF inhibitor monotherapy, and six patients were treated with ICI for advanced melanoma; four patients received adjuvant treatment with nivolumab. Given the few cases and the absence of randomized clinical trials, it is important to report clinical experiences, which can guide physicians in the treatment of melanomas harboring rare BRAF mutations.

We find an extended and conserved CDC37 motif, HPNID---SL--W, responsible for recognizing the C-lobe of BRAF kinase domain, while the c-terminal domain of CDC37 is responsible for the second of the bipartite interaction with BRAF. We show that dimerization of BRAF, independent of nucleotide binding, can act as a potent signal that prevents CDC37 recognition and discuss the implications of mutations in BRAF and the consequences on signaling in a clinical setting, particularly for class 2 BRAF mutations.

The primary endpoint of Part B is PFS, and secondary endpoints include OS, ORR, and DOR. This study has enrolled 43 patients of the planned 228 in Part A at the time of abstract submission.

In our retrospective study we found that among stage III BRAF-mutant patients monotherapy with aPD1 was the most common adjuvant treatment regimen. In some patients with stage III disease IFN-alfa is still given. More studies are needed to define best adjuvant treatment for BRAF mutant stage III melanoma pts.

Of the entire cohort, we observed five activating PIK3CA mutations (R108H; G364R; E542K; E545K, n = 2) which may be sensitive to FDA-approved PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 2), STK11 (n = 1) and PTEN (n = 1) can be targeted with MEK inhibitor selumetinib and mTOR inhibitor everolimus, respectively. Except for one V600E mutation, all mutations in BRAF are either type 2 (L597R, n = 1) or type 3 (N581S, n = 1; D594N, n = 4) which were sensitive to MEK inhibitor trametinib...Interestingly, one IDH1 mutation (R132C) carrier in our cohort might benefit from ivosidenib... Through comprehensive genomic characterization of Chinese SBA patients, we identified actionable variants of multiple signaling pathways in plenty. NGS profiling results can guide physicians to enroll a significant portion of SBA patients in genomically-matched clinical trials.

This is a single center experience from an Indian NSCLC cohort and shows higher prevalence of non-V600E than V600E mutation reported in literature. This may be attributed to increased use of NGS testing revealing otherwise missed alterations on sequential single gene testing.

Our results demonstrate that the Idylla BRAF Mutation Assay produces accurate, precise results in less than 3 hours, with faster TAT compared to NGS. Single-use cartridges eliminate the need for manual sample preprocessing and the risk of PCR contamination. In addition, this sensitive assay correctly identifies BRAF V600 alterations in samples with necrosis and low tumor cell content.

Conclusion Our results - on a small number of patients - suggest that patients with rare BRAF mutations may have inferior survival outcomes with first line targeted treatment, compared with patients with classical BRAF mutations. Impact statement Our findings add to the limited clinical knowledge on rare BRAF mutations in melanoma and may help guide treatment decisions on this small subset of patients.

One patient with V600E mutation received vemurafenib . The other patient with a nonV600E mutation (V600_601delins, detected on NGS) received combination dabrafenib-trametinib with an ongoing partial response at 6 months... This single centre study depicts distinct clinicopathologic features in Indian patients with BRAF mutant NSCLC . The higher prevalence of non-V600E mutation may be attributed to increased use of broader panel based NGS testing as opposed to sequential single gene testing . One of the patients with a non-V600E mutation responded to targeted therapy, hence clinicians should be aware of this spectrum of potentially targetable BRAF mutations.

We also found two MAP2K1 activating mutations (K57E and K57N) which can be targeted by trametinib...We also observed two activating PIK3CA mutations (R108H and G364R) which may be sensitive to PIK3CA inhibitor alpelisib... The mutational landscape of our SBA cohort provided compelling evidence that multiple signaling pathways play a role in the pathogenesis of SBA and many driver mutations in these pathways are targetable. Our findings indicated that SBA patients should participate in matched clinical trials for better management of this disease.

This is the first case of solitary brain metastasis of occult papillary thyroid carcinoma with double mutation of BRAF L597Q and V600E in 2 separate lesions reported in the literature. Our study extends the disease spectrum of occult papillary thyroid carcinoma and suggests that the BRAF L597Q mutation might play a specific role in inducing the solitary brain metastasis of occult papillary thyroid carcinoma in a Chinese Tibetan patient, but the detailed molecular mechanism remains to be confirmed by a large number of functional experiments and clinical research.

In September 2017, lung metastasis was observed and pembrolizumab was started. Progressive disease was apparent at cycle 10 and therapy was switched to ipilimumab...In November 2017, next generation sequencing genomic profiling disclosed a rare L597K-BRAF mutation and vemurafenib plus cobimetinib therapy was initiated in January 2018...Cases of patients with non-V600-BRAF mutations responding to iBRAF/iMEK therapy have been reported over the last years. To the best of our knowledge, this is the first case reporting response to combined iBRAF/iMEK therapy in a patient with metastatic melanoma harboring L597K mutation.

In Xinjiang, China, the difference in ethnicity may be due to the different frequency of melanoma TERT promoter mutations and the distribution ratio of subtypes. TERT promoter mutation associated with BRAF V600E mutations.The combined mutation was significantly associated with more invasive clinicalpathology of melanoma compared to the single mutation, indicating a worse prognosis outcome.

Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.

"In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of VUS more likely to be oncogenic drivers. Our data indicate certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide treatment for BRAF-mutant NSCLC."

The two patients with FGFR2 p.H167_N173del were treated with an FGFR-1/2/3 inhibitor (Debio-1347), and both achieved durable partial response (PR) of over 11 months...The second patient remains on active treatment.Our data show that extracellular domain FGFR2 in-frame indels are rare but targetable novel oncogenic alterations in IHCC. An expanded search of AACR Project GENIE data found 18 extracellular FGFR2 in-frame indels in diverse tumor types, supporting further functional evaluation and clinical targeting of these indels across tumor types.