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Metastatic breast cancer (mBC) is an incurable disease, and it is not sensitive to immunotherapy due to its low immunogenicity. Recently, inactivated DNA polymerase epsilon (POLE) mutations have been found to be associated with high tumor mutational burden (TMB), which is an effective immuno-oncology biomarker. Patients with POLE mutations with different types of cancer have properly responded to immunotherapy. We aimed to report the first case of programmed death-ligand 1 (PD-L1)-negative mBC presenting with high TMB and POLE mutations, in which a complete response to 5 cycles of chemotherapy and 1 year of pembrolizumab and trastuzumab was noted after failing several lines of HER2-targeted therapies. Our findings also suggest that biomarker-driven patient selection is highly significant for further clinical development of combination therapies via anti-HER2 plus immune-checkpoint inhibitors for HER2+ BC patients.

Crizotinib, a multitargeted MET/ALK/ROS1 tyrosine kinase inhibitor, has been approved for the treatment of ROS1 fusion–positive non‐small cell lung cancers (NSCLCs). However, “on‐target” or “off‐target” resistance alterations often emerge that confer the drug resistance. Patients with ROS1‐rearranged NSCLC who develop crizotinib resistance, especially those acquiring “off‐target” resistance mutations, still lack effective therapeutic options for after crizotinib treatment. Herein, we reported a patient with stage IVb lung adenocarcinoma harboring ROS1 fusion, who acquired a BRAF V600E and lost the ROS1 fusion after progression on crizotinib. It was deduced that the V600E may originate from a subclone with an extremely low fraction that was independent of ROS1 fusion–positive cells. The patient was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months. Our study revealed that BRAF V600E can confer the crizotinib resistance in ROS1 fusion–positive NSCLC and presented the first case showing that the treatment with dabrafenib and trametinib can serve as an effective option for later‐line treatment for this molecular‐defined subgroup. Key Points Patients with ROS1‐rearranged non‐small cell lung cancer (NSCLC) who acquire “off‐target” resistance mutations to crizotinib still lack effective therapeutic options for after crizotinib treatment.This report describes the case of a patient with ROS1‐rearranged NSCLC who acquired a BRAF V600E and lost the ROS1 fusion after crizotinib failure.The case was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months.This is the first article reporting that treatment with dabrafenib and trametinib may serve as an effective option for later‐line treatment for patients harboring resistant BRAF V600E., Rearrangements of the ROS1 gene occur in 1%–2% of non‐small cell lung cancers, characterizing a distinct molecular subgroup. This article reports a case of stage IVb lung cancer in a patient with ROS1 fusion who acquired a BRAF V600E fusion after progression on crizotinib.

G724S is a rare mutation induced by different generations of tyrosine kinase inhibitors (TKIs). No clinical effective drugs toward G724S mutation have been reported till now. We analyzed the interaction of three drugs (afatinib, gefitinib, osimertinib) with epidermal growth factor receptor (EGFR) from three aspects: the spatial structure of the binding region, the scoring function value, and the interaction force between drug molecules and active center of EGFR. Our results indicate that afatinib remains effective to patients with EGFR Exon19Deletion(Ex19Del) and G724S mutations whereas osimertinib and gefitinib are not, which is consistent with other reports. Afatinib is reported to be effective against G724S mutation, but no long‐term clinical survival has been reported till now. A patient with stage IV adenocarcinoma was found to have Ex19Del/G724S mutation. Treated with afatinib, he received a progression‐free survival of more than 1 year. With the guidance of this case report, we provide the clinical evidence of using afatinib for patients with G724S mutations and obtaining long‐term clinical survival. Key Points Guided by protein‐drug docking, afatinib is more effective to EGFR G724S mutation compared with osimertinib and gefitinib.A patient with Ex19Del/G724S mutation obtained long‐term survival with afatinib treatment., This brief communication presents the case of a patient with acquired Ex19Del/G724S mutation who was treated with afatinib and obtained long‐term clinical benefit.

Next-generation sequencing (NGS) technologies have become increasingly used for managing breast cancer. In addition to the conventional use of NGS for predicting recurrence risk and identifying potential actionable mutations, NGS can also serve as a powerful tool to understand clonal origin and evolution of tumor pairs and play a unique role in clarifying complex clinical presentations. We report an unusual case of early-stage breast cancer in which the primary tumor and draining axillary node were histologically discordant. The primary tumor was invasive lobular carcinoma, whereas the nodal metastasis was invasive ductal carcinoma. This discordance led us to question whether the tumors had the same origin. NGS performed on both specimens identified no overlapping variants, leading us to conclude that the patient had two separate primary breast cancers, with the nodal tumor representing metastasis from an occult breast cancer. DNA sequencing of the primary tumor and the nodal metastasis allowed us to predict the patient's recurrence risk, and we initiated adjuvant chemotherapy and hormonal therapy based on these results. This case illustrates the utility of NGS for successfully managing a rare and challenging case. KEY POINTS: A degree of molecular concordance is expected for tumors originating from a common stem or progenitor cell. The histological discordance and absence of any genomic overlap should raise suspicion for two separate primary tumors. Paired DNA sequencing of the primary tumor and nodal metastasis can inform clinical decisions when primary breast tumor and axillary metastasis are histologically discordant. Molecular/Precision Oncology Tumor Board is the best setting to facilitate such decisions in these challenging cases. Paired DNA sequencing under these rare circumstances may suggest an occult breast tumor.

Endometrial cancer is the most common gynecologic cancer in the U.S., but metastasis to the brain is rare, and diagnosis can be challenging. Traditional tools for determining if a tumor is a primary or metastatic lesion include pan-imaging, histopathologic studies, and immunohistochemistry. Molecular testing with next-generation sequencing has been increasingly used to augment these tests. We present a case of a patient who initially presented with a brain lesion diagnosed as glioblastoma on histology and immunohistochemistry, but whose diagnosis was later changed to metastasis from an endometrial primary based on molecular findings. The two tumors shared a common microsatellite instability signature and 51 DNA variants, including oncogenic driver mutations KRAS p.G13D, PIK3CA p.E545A, and PTEN p.I135V and p.K267Rfs*9. This highlights the power of molecular analysis in making the diagnosis in cases of rare metastases. Key Points Brain metastasis from endometrial primary is rare, and histopathological features may be augmented with molecular analysis to aid in diagnosis. Comparison of the molecular makeup of the primary endometrial lesion with the metastatic lesion may reveal high-risk molecular features that may be indicative of metastatic potential.

Enhanced understanding of the molecular events underlying oncogenesis has led to the development of “tumor‐agnostic” treatment strategies, which aim to target a tumor's genomic profile regardless of its anatomic site of origin. A classic example is the translocation resulting in an ETV6‐NTRK3 gene fusion, a characteristic driver of a histologically diverse array of cancers. The chimeric ETV6‐NTRK3 fusion protein elicits constitutive activation of the tropomyosin receptor kinase (TRK) C protein, leading to increased cell survival, growth, and proliferation. Two TRK inhibitors, larotrectinib and entrectinib, are currently approved for use in the metastatic setting for the treatment of advanced solid tumors harboring NTRK fusions. Here we report a rare case of recurrent secretory carcinoma of the breast (SCB) with NTRK3 gene fusion. Whereas most cases of SCB represent slow‐growing tumors with favorable outcomes, the case detailed here is the first to the authors' knowledge of recurrence within 1 year of surgery. We review the molecular findings and potential clinical significance. KEY POINTS: The translocation resulting in the ETV6‐NTRK3 gene fusion is a known oncogenic driver characteristic of secretory carcinoma of the breast (SCB). Whereas most cases of SCB represent slow‐growing tumors with favorable outcomes, the case here with ETV6‐NTRK3 gene fusion had local recurrence within 1 year of surgery. Two tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib, are approved to treat NTRK fusion–positive tumors, demonstrating sustained high overall response rates in the metastatic setting. Approval of TRK inhibitors necessitates optimization of NTRK fusion detection assays, including detection with liquid biopsies.

Pembrolizumab, a programmed death 1 ligand (PD-1) checkpoint inhibitor, has elicited responses in mismatch repair (MMR)–deficient advanced solid tumors, leading to its agnostic approval by the US Food and Drug Administration in 2017 when no other therapeutic options are available. However, there are still insufficient data on the response to checkpoint inhibitors in advanced endometrial cancer related to Lynch syndrome (LS) and, specifically, in uterine serous carcinoma, which is uncommon in LS. Here we report a case of metastatic uterine serous carcinoma due to a germline MSH6 mutation (Lynch syndrome) that was discovered because of a patient's tumor MMR deficiency. The patient was started on first-line pembrolizumab in 2018 and sustained a partial response. She remains asymptomatic and progression free for more than 2 years. Tumor sequencing showed a high mutational burden and an upstream somatic mutation in the same gene, p.F1088fs. Immunohistochemical staining was negative for PD-L1 expression. We discuss clinical characteristics of the patient, molecular features of her tumor, and the mechanism of her tumor response. We also discuss the duration of immunotherapy in her case. Our case demonstrated a partial response and a long-term remission from the frontline single-agent pembrolizumab in a woman with metastatic uterine serous carcinoma and Lynch syndrome due to a germline MSH6 gene mutation. Our experience suggests a potential significant clinical benefit of checkpoint inhibitors used as single agents early on in the treatment of MMR-deficient/high microsatellite instability/hypermutated uterine cancers in women with Lynch syndrome. Key Points Even though checkpoint inhibitors are effective in mismatch repair-deficient endometrial cancer, it is unknown whether the response to them differs between women with endometrial cancer due to germline mutations in a mismatch repair gene (Lynch syndrome) and women with sporadic endometrial cancer. In our case, a patient with Lynch syndrome and recurrent mismatch repair-deficient serous endometrial cancer achieved a durable remission on the first-line therapy with the checkpoint inhibitor pembrolizumab and remains progression free after more than 2 years. Based on our observation and the data, suggesting the stronger immune activation in women with Lynch syndrome–associated endometrial cancer, we propose to use checkpoint inhibitor monotherapy early in the course of their treatment and stratify patients for the presence of Lynch syndrome in clinical trials.

Rearrangements involving the neurotrophic receptor tyrosine kinase (NTRK) gene family have been reported in diverse tumor types, and NTRK‐targeted therapies have recently been approved. In this article, we report a case of a 26‐year‐old man with an NTRK2‐rearranged isocitrate dehydrogenase‐wild‐type glioblastoma who showed a robust but temporary response to the NTRK inhibitor larotrectinib. Rebiopsy after disease progression showed elimination of the NTRK2‐rearranged tumor cell clones, with secondary emergence of a PDGFRA‐amplified subclone. Retrospective examination of the initial biopsy material confirmed rare cells harboring PDGFRA amplification. Although mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma has been previously described, mosaicism involving a fusion gene driver event has not. This case highlights the potential efficacy of NTRK‐targeted treatment in glioblastoma and the implications of molecular heterogeneity in the setting of targeted therapy. Key Points This case highlights the efficacy of the NTRK inhibitor larotrectinib in treating NTRK‐rearranged glioblastoma. This is the first case to demonstrate mosaicism in glioblastoma involving both a fusion gene and amplification for receptor tyrosine kinases. Intratumoral heterogeneity in glioblastoma has significant implications for tumor resistance to targeted therapies.

Perioperative chemotherapy is standard treatment for patients with early high‐risk gastroesophageal adenocarcinoma independent of molecular subtype. Approximately 8% of gastroesophageal cancers have a microsatellite instable phenotype (MSI‐H), and retrospective analyses of neoadjuvant/adjuvant chemotherapy trials suggests no survival benefit in this patient population compared with surgery alone. Patients with advanced MSI‐H malignancies obtain durable responses with immunotherapy using anti–programmed cell death protein 1 (PD‐1) checkpoint blockade. We describe a case of a patient with an early MSI‐H gastroesophageal adenocarcinoma who progressed on neoadjuvant chemotherapy precluding subsequent surgical resection. The patient was subsequently treated with immunotherapy using the anti–PD‐1 antibody nivolumab and the anti–cytotoxic T‐lymphocyte–associated protein 4 (CTLA‐4) antibody ipilimumab leading to a complete remission with biopsies of the residual tumor mass and regional lymph nodes revealing no residual tumor. This case highlights the lack of benefit from neoadjuvant chemotherapy in patients with MSI‐H gastroesophageal cancers and suggests that perioperative anti–PD‐1–based immunotherapy should be further investigated in this patient population. KEY POINTS: This report describes the successful salvage treatment of a patient with an early high‐risk MSI‐H gastroesophageal carcinoma who progressed through neoadjuvant chemotherapy using combination immunotherapy of the anti–programmed cell death protein 1 (PD‐1) antibody nivolumab and the anti–cytotoxic T‐lymphocyte–associated protein 4 (CTLA‐4) antibody ipilimumab, leading to an ongoing complete remission. The case is in keeping with retrospective analyses of perioperative treatment trials demonstrating a lack of chemotherapy benefit in patients with MSI‐H gastroesophageal carcinoma and supports the further investigation of anti–PD‐1–based immunotherapy as a treatment modality in this patient population. The case highlights the potential difficulties that may be encountered in the surgical management of patients treated with neoadjuvant immunotherapy with reactive dense fibrotic changes precluding surgical resection.

Cystic lymphangioma are rare benign vascular or lymphatic tumors, diagnosed mostly in newborns or children, that may become life‐threatening because of local invasiveness. Surgical “en‐bloc” resection with negative margins is the only curative treatment, but some patients are diagnosed with unresectable tumors. We describe the case of a young adult with giant unresectable mesenteric lymphangioma. Extensive pathological characterization as well as whole exome and transcriptome sequencing enabled us to identify mTOR pathway activation within endothelial tumor cells. The patient was treated with everolimus and experienced major partial response, leading to the surgical resection of the residual lesions. This case highlights the importance of molecular characterization of adult cystic lymphangioma for mTOR pathway activation because multidisciplinary therapeutic approaches, including neoadjuvant everolimus and secondary surgery, can lead to complete cure of this rare condition. KEY POINTS: The case of an adult patient diagnosed with giant unresectable mesenteric cystic lymphangioma, in which activation of the mTOR pathway was documented at both the pathological and transcriptomic levels, is reported. This patient showed major partial response to the mTOR inhibitor everolimus, which led to the successful resection of residual tumor lesions after 9 months of treatment. This report shows that mTOR targeting should be considered as neoadjuvant treatment in adult large cystic lymphangioma, as it can lead to complete surgery and cure of this rare condition.

Identifying the druggable target is crucial for patients with nonsquamous advanced non‐small cell lung cancer (NSCLC). This article adds to the spectrum of ROS1 fusion cases described in NSCLC. We describe a novel SLC12A2‐ROS1 rearrangement that has not been previously reported in other cancers: a fusion that has clinical and radiological sensitivity to crizotinib. Fluorescence in situ hybridization detected the SLC12A2‐ROS1 fusion and it was confirmed through hybrid capture‐based next‐generation sequencing (NGS); however, the fusion could not be detected by amplicon‐based assay. The success of implementing NGS into routine clinical practice depends on the accuracy of testing. The test's methodological features should then be considered because they significantly affect the results. Given this patient's response to crizotinib, identifying patients with undescribed ROS1 fusions has important therapeutic implications. Key Points This is the first known description of an SLC12A2‐ROS1 fusion. Considering the patient's clinical features and tumor response observed after crizotinib therapy, the authors confirm that this new rearrangement has relevant clinical impact for patients with non‐small cell lung cancer.The success of implementing next‐generation sequencing (NGS) into routine clinical practice depends on the accuracy of the testing. Different assays and NGS platforms can achieve differing results. Each assay's limitations need to be considered to ensure the quality of precision medicine in clinical practice., This case report is the first known report of an SLC12A2‐ROS1 fusion in non‐small cell lung cancer and describes the clinical features and tumor response observed after crizotinib therapy.

Somatic mutations in human epidermal growth factor receptor 2 (HER2) are present in approximately 3% of breast cancers. Some HER2 mutations are activating, and they represent a mechanism of resistance to conventional anti-HER2 therapies such as trastuzumab and lapatinib. Consistently, in patients with HER2-amplified breast cancer, these mutations are predominantly observed in metastatic tumors obtained after exposure to anti-HER2 systemic therapies, possibly after clonal selection. Therefore, it is rare to find coexistent HER2 mutation and amplification in the early clinical course, and thus, the clinical relevance of HER2 mutation to the sensitivity to HER2-targeted drugs, particularly antibody-drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and the recently approved fam-trastuzumab deruxtecan (T-DXd), remains unclear. In this article, we describe a patient with de novo metastatic breast cancer who exhibited both HER2 amplification and the L755S mutation in the untreated primary breast tumor obtained at the initial diagnosis, and the lesion responded to T-DM1 and T-DXd after exhibiting clinical resistance to other HER2-targeted drugs. Our current case findings suggested that anti-HER2 ADCs should be prioritized over conventional trastuzumab- or lapatinib-based therapies for patients with HER2-amplified and comutated tumors. Key Points Although HER2 mutations were implicated in resistance to anti-HER2 monoclonal antibodies or HER2 tyrosine kinase inhibitors in preclinical studies, their clinical impact on sensitivity to anti-HER2 drugs is unclear owing to the rarity of concomitant HER2 mutation and HER2 amplification. A case of de novo metastatic breast cancer harboring both HER2 amplification and the L755S mutation in an untreated breast primary tumor displayed clinical resistance to standard trastuzumab- or lapatinib-based therapies but good responses to ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd). Anti-HER2 antibody-drug conjugates such as T-DM1 and T-DXd may be prioritized over conventional trastuzumab- or lapatinib-containing therapies for patients with HER2-amplified and comutated tumors.

Myxofibrosarcoma (MFS) is a well‐recognized histotype of soft tissue sarcomas that generally presents with localized disease. Herein, we describe the case of a patient with metastatic MFS who experienced durable response to sixth‐line therapy with temozolomide. Upon further progression, his tumor was notable for a high tumor mutational burden, and he was subsequently treated with seventh‐line immunotherapy, atezolizumab, achieving a second durable response. This case highlights the role of immunotherapy after administration of alkylating agents. Review of the literature indicates that recurrent tumors treated with alkylating agents often experience hypermutation as a means of developing resistance and that checkpoint inhibitors are subsequently effective in these tumors. KEY POINTS: To the authors' knowledge, this is the first report of a patient with myxofibrosarcoma with high tumor mutational burden after administration of temozolomide monotherapy. Hypermutation may be a resistance mechanism for patients with soft tissue sarcoma who develop resistance to alkylating agents. Checkpoint inhibition may be effective therapy in patients with soft tissue sarcoma with high tumor mutational burden as a consequence of alternate systemic therapy resistance.

We report on a woman with aggressive estrogen receptor‐positive, KRAS‐mutated ovarian cancer who achieved a remarkable response to combination therapy with the MEK inhibitor (trametinib) and the aromatase inhibitor (letrozole), even though the disease had failed to respond to a combination of a PI3K inhibitor and different MEK inhibitor, as well as to trametinib and the estrogen modulator, tamoxifen, and to letrozole by itself. The mechanism of action for exceptional response was elucidated by in vitro experiments that demonstrated that the fact that tamoxifen can have an agonistic effect in addition to antagonist activity, whereas letrozole results only in estrogen depletion was crucial to the response achieved when letrozole was combined with an MEK inhibitor. Our current observations indicate that subtle variations in mechanisms of action of outwardly similar regimens may have a major impact on outcome and that such translational knowledge is critical for optimizing a precision medicine strategy. Key Points This report describes the remarkable response of a patient with KRAS‐mutated, estrogen receptor‐positive low‐grade serous ovarian cancer treated with trametinib (MEK inhibitor) and letrozole (aromatase inhibitor), despite prior progression on similar agents including tamoxifen (estrogen modulator).In vitro investigation revealed that tamoxifen can have agonistic in addition to antagonistic effects, which could be the reason for the patient not responding to the combination of trametinib and tamoxifen.The current observations suggest that drugs with different mechanisms of action targeting the same receptor may have markedly different anticancer activity when used in combinations., This article reports the case of a patient with aggressive estrogen receptor‐positive, KRAS‐mutated ovarian cancer who achieved a remarkable response to combination therapy with the MEK inhibitor trametinib and the aromatase inhibitor letrozole, despite earlier failures of treatment with other combination inhibitor treatment. This article focuses on the possibility that subtle variations in mechanisms of action of outwardly similar regimens may have major effects on patient outcomes.

Recently, several malignant peritoneal mesotheliomas (MPMs), occurring in young women without asbestos exposure and with fusion genes such as anaplastic lymphoma kinase (ALK) and Ewing sarcoma breakpoint region 1, have been reported. In the present case, we encountered MPM with STRN-ALK fusion in a 17-year-old female adolescent. The case did not respond to chemotherapy and is currently in a clinical trial of alectinib. This is the fourth reported case of MPM with STRN-ALK fusion. Of the 45 cancer cases with STRN-ALK fusion in which the fusion partners were examined, all cases except for the current case showed fusion of exon 3 of STRN and exon 20 of ALK. This is the first case with fusion of exon 2 of STRN and exon 20 of ALK. Further advances in cancer genomic medicine may help clarify the clinical significance of this new fusion. Key Points Malignant peritoneal mesotheliomas (MPMs) can occur in young women without asbestos exposure and show fusion genes that activate anaplastic lymphoma kinase (ALK) by gene rearrangement. ALK rearrangement and the fusion partner can be detected by companion diagnostics and by next generation sequencing. Patients with MPMs with ALK rearrangement may benefit from target therapy.

We describe a case of recurrent glioblastoma treated with anlotinib in this report. The patient was administered anlotinib 12 mg p.o. once every day (days 1–14, with a 21-day cycle) (anlotinib clinical study NCT04004975) and oral temozolomide chemotherapy 100 mg/m2 (days 1–7, days 15–21, 28-day cycle; 12 cycles). After 2 months of therapy, the patient achieved a partial response that has been maintained for >17 months of follow-up. Molecular characterization confirmed the presence of a TERT promoter mutation, wild-type IDH1/2, an FGFR3-TACC3 fusion, and FGFR3 amplification in the patient. Anlotinib is a multitarget tyrosine kinase inhibitor that was originally designed to inhibit VEGFR2/3, FGFR1–4, PDGFRα/β, and c-Kit. Patients with TERT promoter mutations and high-grade IDH-wild-type glioma have shorter overall survival than patients with IDH-wild-type glioma without TERT promoter mutations. However, this patient had a favorable clinic outcome, and FGFR3-TACC3 fusion may be a new marker for treatment of glioma with anlotinib. Key Points This case study is believed to be the first report that FGFR3-TACC3 fusion could be a novel indication to treat recurrent glioblastoma with the drug anlotinib. This case exhibited an exceptional response (maintained partial response >17 months) after 2-month combined therapy of anlotinib and oral temozolomide chemotherapy. This case also underscores the importance of molecular diagnosis for clinically complex cases. Tumor tissue-based assessment of molecular biomarkers in brain tumors has been successfully translated into clinical application.

Melanoma can be classified based on the detection of relevant oncogenic driver mutations. These mutations partially determine a patient's treatment options. MEK inhibitors have demonstrated little efficacy in patients with NRAS‐mutated melanoma owing to primary and secondary resistance. We report two patients with NRAS‐mutant metastatic melanoma with long‐term response to intermittent MEK‐inhibitor binimetinib therapy. Intermittent dosing schedules could play a key role in preventing resistance to targeted therapy. This article highlights the efficacy of an intermittent dosing schedule, toxicities associated with binimetinib, and possible mechanisms preventing resistance in targeted therapy. Intermittent MEK‐inhibitor therapy may be considered in patients with NRAS‐mutated melanoma that have failed all standard therapies. Key Points Melanomas harbor NRAS mutations in 10%–30% of the cases. These mutations promote hyperactivation of the MAPK pathway, leading to proliferation and prolonged survival of tumor cells.Currently, drugs directly targeting NRAS are not available. Downstream inhibition of the MAPK pathway can be considered as a therapeutic option after immunotherapeutic failure.Intermittent administration of kinase inhibitors might be the way to partially overcome the development of drug resistance by (a) inducing a fitness deficit for drug‐resistant cells on treatment break, (b) increasing the immunogenicity, and (c) inducing apoptosis and cell cycle arrest. It also enhances expression of numerous immunomodulating molecules, and reduction of immunosuppressive factors, which suggests better access of the immune system to the tumor., Case reports for two patients with NRAS‐mutant metastatic melanoma are presented, highlighting toxicities associated with binimetinib, as well as the efficacy of an intermittent dosing schedule and possible mechanisms preventing resistance in targeted therapy.

The addition of immune checkpoint inhibitors to the armamentarium of cancer therapies has resulted in unprecedented improvement in clinical outcomes for a vast range of malignancies. Because they interfere with the physiologic function of immune checkpoints, such as programmed cell death protein 1 or cytotoxic T-lymphocyte-associated protein 4, to promote self-tolerance, these agents are associated with a unique spectrum of immune-related adverse events (irAEs). Immune-mediated endocrinopathies are among the most commonly noted irAEs. Immune-mediated diabetes is an uncommon irAE but can be associated with significant morbidity if it is not recognized and treated in a time-sensitive manner. In this manuscript, we present a case based discussion and review of the literature pertaining to immune-mediated diabetes associated with immune checkpoint blockade. Key Points Immune checkpoint inhibitor associated diabetes mellitus often resembles type 1 diabetes mellitus (DM) in its pathophysiology and clinical manifestations. However, some patients may present with type 2 DM or worsening hyperglycemia in the setting of pre-existent DM. Early recognition and management is key to preventing life-threatening events such as diabetic ketoacidosis. Endocrinology referral and interdisciplinary management should be considered for every patient to optimize glycemic control and to ensure optimal monitoring for long-term microvascular complications.

Since its discovery in 2007, we have seen the lives of patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLC) transform with the advent of molecular therapies with first-, second-, and third-generation ALK inhibitors now available in the clinic. Despite great gains in patient survival now measured in years and preserved quality of life with targeted therapies, drug resistance is unfortunately inevitably encountered in this rare and unique molecular subset of lung cancer, and patients will eventually succumb to the disease. As these patients are often young, fit, and never smokers, the clinical and scientific communities have aligned to expedite drug development and access. Drug resistance profiling and further strategies are being explored through clinical trials, including the evaluation of specific drug sequencing and combinations to overcome such resistance and promote patient longevity. The cases of this report focus on precision medicine and aim to portray the pertinent aspects to consider when treating ALK-rearranged NSCLC in 2020, an ever-shifting space. By way of case examples, this report offers valuable information to the treating clinician, including the evolution of systemic treatments and the management of oligo-progression and multisite drug resistance. With the maturation of real-world data, we are fortunate to be experiencing quality and length of life for patients with this disease surpassing prior expectations in advanced lung cancer. Key Points This report focuses on the importance of genetic analysis of serial biopsies to capture the dynamic therapeutic vulnerabilities of a patient's tumor, providing a perspective on the complexity of ALK tyrosine kinase inhibitor (ALKi) treatment sequencing. These case examples contribute to the literature on ALK-rearranged and oncogene addicted non-small cell lung cancer (NSCLC), providing a framework for care in the clinic. In oligo-progressive disease, local ablative therapy and continuation of ALKi postprogression should be considered with potential for sustained disease control. ALK G1202R kinase domain mutations (KDM), highly prevalent at resistance to second-generation ALKi resistances, may emerge in non-EML4-ALK variant 3 cases and is sensitive to third-generation lorlatinib. When in compound with one or more ALK KDMs, resistance to lorlatinib is expected. In the case of rampantly progressive disease, rebiopsy and redefining biology in a timely manner may be informative.

Sinonasal tumors consist of a group of rare heterogeneous malignancies, accounting for 3%–5% of all head and neck cancers. Although squamous cell carcinomas make up a significant portion of cancers arising in the sinonasal tract, there are a variety of aggressive tumor types that can present with a poorly differentiated morphology and continue to pose diagnostic challenges. Accurate classification of these unique malignancies has treatment implications for patients. Recent discoveries have allowed more detailed molecular characterization of subsets of these tumor types, and may lead to individualized treatments. INI-1 (SMARCB1)–deficient sinonasal carcinoma is a recently identified subtype of sinonasal malignancy, which is characterized by deletion of the INI-1 tumor suppressor gene. Loss of INI-1 expression has emerged as an important diagnostic feature in several human malignancies including a subset of sinonasal carcinomas. In this article, we present a case of INI-1 (SMARCB1)–deficient sinonasal carcinoma, provide an overview of recent advances in histological and molecular classification of sinonasal malignancies, and discuss challenges of caring for patients with these rare malignancies, as well as potential treatment implications. Key Points Clinicians and pathologists should recognize that a variety of sinonasal tumors can present with a poorly differentiated morphology that warrants further workup and molecular classification. Routine workup of poorly or undifferentiated sinonasal tumors should include testing for INI-1/SMARCB1, SMARCA4, and NUT. Patients with these molecularly defined subsets of tumors may benefit from clinical trials that seek to exploit these molecular alterations. The EZH2 inhibitor, tazemetostat, has demonstrated some antitumor activity in INI-1–deficient tumors, and is currently under investigation.

Background The identification of epidermal growth factor receptor (EGFR) mutations represents a milestone in the treatment of advanced non-small cell lung cancer. Patients with lung adenosquamous carcinomas (ASCs) rarely present with germline EGFR T790M mutation. The optimal treatment for cancers with germline EGFR T790M mutation (especially ASC) is not clear. Materials and Methods Using next-generation sequencing, we tested 450 cancer-related genes in a 27-year-old patient's lung adenosquamous carcinoma and matched blood samples. Germline mutations in samples from the patient's available relatives were identified by Sanger sequencing. Results We identified germline EGFR T790M mutation in the patient's lung adenosquamous carcinoma. He was treated with osimertinib and achieved complete response for more than 30 months, without significant drug-related adverse events. Genetic testing showed that germline EGFR T790M mutation might be a characteristic of inherited lung cancer. Conclusion Osimertinib can be a treatment option for patients with lung ASC harboring germline EGFR T790M mutation. Key Points A patient with adenosquamous carcinoma harboring a germline T790M mutation responded well to osimertinib with a progression-free survival of more than 30 months and without any unexpected toxicities. Osimertinib is effective for patients with lung squamous cell carcinoma with T790M and L858R mutations. The germline EGFR T790M mutation is associated with genetic susceptibility to lung cancer. The clinical use of next-generation sequencing could maximize the benefits of precision medicine in patients with cancer.

Background Increasing knowledge about the genomic changes underpinning cancer development and growth has led to a rapidly expanding number of individualized therapies that specifically target these changes in a patient's tumor. Here we present a case report of a patient with metastatic esophageal carcinoma whose tumor harbored NTRK1 gene amplification and who received targeted systemic therapy with larotrectinib. At initial diagnosis, the patient presented with tumor obstruction of the middle esophagus, simultaneous liver and lung metastases, UICC IV and WHO performance status 3. Materials and Methods The solid tumor genomic profiling test FoundationOne CDx (F1CDx) was used to detect clinically relevant genomic alterations that, in turn, might identify a targeted therapeutic approach if suggested by the findings. The patient was then treated with larotrectinib and had subsequent follow‐up biopsies. Results Simultaneous biopsies of the primary tumor and liver lesions identified a metastatic squamous cell esophageal carcinoma. Comprehensive genomic profiling obtained from liver metastases identified numerous genomic alterations including amplification of NTRK1. Owing to the reduced performance status of the patient, chemotherapy could not be applied and was denied. Although larotrectinib is only approved for the treatment of cancers with NTRK gene fusions, treatment was started and led to a shrinkage of the primary tumor as well as the liver and lung metastases within 6 weeks according to RECIST criteria accompanied by tumor marker decrease. The NTRK1 gene amplification was below the limit of detection in a subsequent liver biopsy. Conclusion The use of comprehensive genomic profiling, specifically F1CDx, enabled the selection of a targeted therapy that led to a rapid reduction of the tumor and its metastases according to RECIST criteria. This case suggests that larotrectinib is not only effective in NTRK fusions but may be efficacious in cases with gene amplification. Key Points Advances in precision medicine have revolutionized the treatment of cancer and have allowed oncologists to perform more individualized therapy.This case shows that larotrectinib could also be effective in cases of NTRK amplification of cancer.Today, there is only limited knowledge about NTRK alterations in squamous epithelial carcinoma of the esophagus. Longitudinal tumor sequencing during the course of the disease may allow for the detection of a molecular genetic cause once the tumor progresses. Additional actionable gene alterations may then be identified, which may provide the rationale for a therapy switch., Knowledge of the efficacy of targeted therapy for TRK gene amplification is still lacking. This report presents the case of a patient with metastatic squamous cell esophageal carcinoma with NTRK1 gene amplification who received targeted therapy with larotrectinib with promising results.

For pediatric patients with high‐grade gliomas, standard‐of‐care treatment includes surgery, chemotherapy, and radiation therapy; however, most patients ultimately succumb to their disease. With advances in genomic characterization of pediatric high‐grade gliomas, the use of targeted therapies in combination with current treatment modalities offer the potential to improve survival in this patient population. In this report, we present the case of a 3‐year‐old girl with glioblastoma who continues to experience an exceptional and durable response (>2 years) to the poly (ADP‐ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal‐parietal‐temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling demonstrated absence of any BRAF or H3F3A mutations. Genomic profiling, however, did reveal a probable germline heterozygous BRCA2 Lys3326Ter (K3226*) nonsense variant. After debulking surgery, the patient received standard‐of‐care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed reduction in tumor size. Since completion of the regimen, the patient remains neurologically intact with no evidence of tumor recurrence. To our knowledge, this represents the first case of a pediatric glioblastoma that maintains a durable response to a therapeutic strategy that included the PARP inhibitor olaparib and more generally highlights the potential clinical utility of incorporating these agents into the treatment of pediatric high‐grade gliomas. Key Points Germline mutations detected in pediatric gliomas may represent a cancer predisposition syndrome.Integrating molecular testing into routine clinical care for pediatric patients with glioma is critical to identify therapeutic targets and patients with a cancer predisposition syndrome.Patients with glioma with defects in DNA repair pathway components (e.g., BRCA1/2) may show increased responsiveness to poly (ADP‐ribose) polymerase (PARP) inhibitors.Combining PARP inhibitors with temozolomide (standard‐of‐care treatment) revealed no adverse events or toxicities over the course of 18 months., This article reports the first case of a pediatric glioblastoma that maintained a durable response to a therapeutic strategy that included the PARP inhibitor olaparib, highlighting the potential clinical utility of incorporating these agents into the treatment of pediatric high‐grade gliomas.

Background Patients with colorectal carcinoma and high‐grade microsatellite instability (MSI‐H) or deficiency in mismatch repair (dMMR) exceptionally respond to immune checkpoint inhibitors (ICIs). ICIs are more active in treatment‐naïve patients than in patients with refractory MSI‐H/dMMR metastatic colorectal cancer and even more active in patients with locally advanced tumors. Material and Methods A 33‐year‐old male patient with Lynch syndrome was diagnosed with a locally advanced rectal cancer and refused standard neoadjuvant chemoradiation because of the potential harm of sexual dysfunction. MMR and microsatellite instability status were analyzed by immunohistochemistry and fragment length polymerase chain reaction followed by capillary electrophoresis. Results After MSI‐H/dMMR was confirmed, the patient was treated with ICIs (1 mg/kg ipilimumab at day 1 and 3 mg/kg nivolumab at day 1 and 15). A complete clinical response was documented at day 21 after start of treatment. The patient underwent a total mesorectal excision at day 30. In the extirpated tissue, a complete pathological response was confirmed. Conclusion In MSI‐H/dMMR locally advanced rectal cancer short‐course ICI treatment is highly effective and may be discussed in patients with dMMR locally advanced rectal cancer. Key Points Immune checkpoint inhibitors are more active in treatment‐naïve patients than in patients with refractory high‐grade microsatellite instability (MSI‐H)/deficiency in mismatch repair (dMMR) colorectal cancer.Standard neoadjuvant chemoradiation is less effective in MSI‐H/dMMR rectal cancer patients than in patients with proficient mismatch repair.A young patient with Lynch syndrome and MSI‐H/dMMR locally advanced rectal cancer refused chemoradiation in order to preserve his fertility.After neoadjuvant treatment with one dose of ipilimumab and two doses of nivolumab a complete clinical and pathological response was documented.Clinical trials are needed to first establish neoadjuvant treatment with immune checkpoint inhibitors in patients with locally advanced MSI‐H/dMMR rectal cancer and thereafter to evaluate organ‐preservation strategies., This report describes the case of a 33‐year‐old male patient with Lynch syndrome who was diagnosed with locally advanced rectal cancer. Instead of chemoradiation, neoadjuvant treatment with immune checkpoint inhibitors was given.

Despite the commonness of prostate cancer in American men, there is a poor understanding of biomarkers that predict responsiveness to immunotherapeutic agents such as the PD‐1 and PD‐L1 inhibitors. This article describes a case of complete remission with pembrolizumab therapy in a patient with metastatic castrate‐resistant prostate cancer with a complex germline MSH2 alteration., Prostate cancer is the second leading cause of cancer death in American men. Despite the common nature of this disease, there is a poor understanding of biomarkers that predict responsiveness to immunotherapeutic agents such as the programmed death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) inhibitors. Herein we describe a case of complete remission with pembrolizumab therapy in a metastatic castrate‐resistant prostate cancer patient with a complex germline MSH2 alteration (Boland inversion) in association with a tumor demonstrating high microsatellite instability. Potential utility of high mutational burden assessed by an experimental circulating tumor DNA assay is also shown. The literature concerning biomarkers for PD‐1 inhibition is reviewed, including data for various mismatch repair gene deficiencies, microsatellite instability, tumor mutational burden, PD‐L1 3' untranslated region mutations, selected POLE mutations, and biallelic CDK12 mutations. Taken together, although prostate cancer is generally believed to be a tumor unresponsive to PD‐1 inhibition, careful dissection of tumor biology is able to provide an approach toward predictive biomarkers that has the potential for expanded clinical utility. Key Points. Biomarkers for anti‐PD1 and anti‐PDL1 therapy are poorly defined in prostate cancer.Recent advances are defining new important classes of responsive patients.

Primary brain tumors are a leading cause of cancer-related morbidity and mortality in children. Glioblastoma (GBM) is a high-grade astrocytoma that occurs in both children and adults and is associated with a poor prognosis. Despite extensive study in recent years, the clinical management of these tumors has remained largely unchanged, consisting of surgical resection, conventional chemotherapy, and radiotherapy. Although the etiology and genomic drivers in GBM are diverse, constitutional mismatch repair-deficiency (CMMRD) syndrome is a rare, recessively inherited disease with a predisposition to gliomagenesis. CMMRD results from biallelic mutations in one of the mismatch repair genes including mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and post-meiotic segregation increased 2 (PMS2). In this report, we present the case of a 5-year-old female with GBM and CMMRD due to an MSH6 homozygous c.1883G>A mutation, who continues to experience an exceptional and durable response (9 months) to the immune checkpoint inhibitor (ICPI) nivolumab. Our patient presented with acute neurologic decline and increased intracranial pressure. Neuroimaging studies revealed a large left frontoparietal mass requiring neurosurgical decompression and resection. Histopathologic analyses resulted in a diagnosis of de novo GBM that was BRAF wild type and negative for programmed death-ligand 1 protein expression. She received standard-of-care treatment with surgery, radiation therapy, and temozolomide; however, the tumor recurred 3 months after the initial diagnosis. Molecular analyses of tumor and blood tissues revealed an MSH6 homozygous c.1883G>A mutation consistent with CMMRD. Given her CMMRD status, she was treated with nivolumab (3 mg/kg doses every 2 weeks for 36 weeks) and showed a 60% reduction in tumor size, improved clinical symptoms, and an ongoing durable response lasting 10 months to date. Our study highlights a durable response to the ICPI nivolumab in a pediatric patient with recurrent/refractory CMMRD-associated GBM. We show that incorporating genomic and/or molecular testing for CMMRD into routine pediatric oncology clinical care can identify a subset of patients likely to benefit from ICPI. Key Points Constitutional mismatch repair-deficiency (CMMRD) syndrome, alternatively known as biallelic mismatch repair deficiency syndrome, occurs in subset of pediatric cancer patients, including those with primary brain tumors. Patients from Arab and other developing countries are predicted to have higher incidence of CMMRD due to high prevalence of consanguinity. Integration of molecular and/or genomic testing into routine clinical care for pediatric cancer patients is important to identify patients with CMMRD syndrome. Patient with CMMRD-associated cancers may show increased responsiveness to immune checkpoint inhibitors. To the authors' knowledge, this is the first report in the Arab world of a durable response to immune checkpoint inhibitors in a pediatric glioblastoma patient.

With the advent of precision medicine, medical oncology is undergoing a transcendental change. These molecular studies have allowed us to learn about potential targeted therapies for patients with advanced cancers. Perhaps the best-known example of success in precision medicine is chronic myeloid leukemia and its response to tyrosine kinase inhibitors targeting the BCR-ABL kinase. Since that original discovery, the role of molecular therapeutics has expanded, and it now presents us with treatment options for common malignancies and rare atypical tumors. In this article, we present a case of a 61-year-old female with a recurrent pulmonary inflammatory myofibroblastic tumor. Subsequent molecular studies revealed an ALK rearrangement. The significance of this alteration in this tumor type and its therapeutic implications are discussed herein. Key Points This case exemplifies the heterogeneous behavior of inflammatory myofibroblastic tumors (IMTs) and the current role of targeted therapy in the therapeutic armamentarium of neoplastic processes. As evidenced by the different mutations found in IMTs, it is of great importance to perform next-generation sequencing in uncommon neoplasms. These studies can find different potential targets and therapeutic options for patients devoid of standard effective therapies.

A challenge in counseling patients with a family history suggesting a hereditary cancer syndrome is deciding which genetic tests or panels to order. In this article, we discuss the identification of multiple familial mutations through genetic counseling and panel testing. For patients meeting National Comprehensive Cancer Network criteria for clinical genetic testing, providers should consider expanded panels to provide a more complete assessment of one's genetic risk. The continued use of expanded panel testing in the clinical setting will help inform optimal management of cancer patients, as well as the management of their unaffected family members. The mutation discovered in this case was in the ATM gene. The clinical significance of the mutation, potential therapeutic targets, and proper clinical management are discussed. Key Points With single-site genetic testing, there is the potential to miss hereditary genetic syndromes that can be managed clinically. Between 4% and 6% of hereditary breast and ovarian cancer syndromes are caused by genes other than BRCA1 and BRCA2. ATM is a DNA mismatch repair gene associated with double-stranded DNA break repair and cell cycle checkpoint arrest. The risk of developing female breast cancer by age 50 and by age 80 in ATM heterozygotes is 9% and 17%–52%, respectively.

Gynecologic carcinosarcomas, previously known as malignant mixed Müllerian tumors, are uncommon malignancies that demonstrate an aggressive biology and lack a standard therapeutic approach. Molecular analyses have revealed recurrent alterations in chromatin remodeling genes, but clinical support for therapeutic significance is lacking. We prospectively identified a patient with refractory uterine carcinosarcoma whose tumor was subject to molecular profiling at diagnosis and again at radiographic progression. Initial molecular testing did not assess tumor mutational burden, DNA polymerase ? (POLE), or microsatellite status. After the failure of several lines of chemotherapy, comprehensive genomic profiling of a repeat biopsy identified two missense mutations of the exonuclease domain of POLE (P286R and T323A). Tumor mutational burden was elevated (169 mutations per DNA megabase), consistent with an ultramutator phenotype. As seen in previously reported POLE-endometrioid cases, our patient harbored alterations in PIK3CA, ARID1A, and PTEN and was microsatellite stable, with appreciable tumor-infiltrating lymphocytes. She achieved an ongoing durable response with pembrolizumab. This is the first report of programmed cell death protein 1 response in uterine carcinosarcoma. Key Points Uterine carcinosarcoma is an uncommon and aggressive histologic variant of endometrial carcinoma with a poor prognosis. Inactivating DNA polymerase ? (POLE) mutations have been associated with high tumor mutational burden (TMB) and response to immune checkpoint inhibition. To the authors' knowledge, this is the first report of response to immune checkpoint inhibitor therapy in a patient with uterine carcinosarcoma. This case further supports expanding genomic profiling to include assessment of tumor mutational burden across tumor types, given the potential for immune checkpoint inhibitor therapy in TMB-high tumors.

Choosing the optimal therapy for a patient's cancer has long been based on whether the cancer demonstrates a predictive marker of efficacy. The U.S. Food and Drug Administration (FDA) has now approved use of a targeted therapy based solely on tumor molecular markers (pembrolizumab for tumors with deficient mismatch repair [MMR] and high microsatellite instability [MSI]) and approved another therapy based solely on a germline mutation as the predictive marker of benefit (olaparib for BRCA carriers with ovarian or breast cancer) [New Engl J Med 2017;377:1409–1412, N Engl J Med 2012;366:1382–1392, N Eng J Med 2017;377:523–533]. Here, a patient is presented with a molecular diagnosis of Lynch syndrome and with breast cancer. Yet the breast cancer showed proficient expression of the same MMR gene found to be mutated in her germline testing. The case underscores the importance of tumor testing for MMR and MSI and of not assuming that the tumor is related to the Lynch syndrome rather than being sporadic. This is particularly true in patients with cancers (e.g., breast cancer) whose association with Lynch syndrome is not well established. The case presented also underscores the importance of considering next-generation sequencing of the tumor when the therapies approved are based on a germline mutation being the predictive marker. For example, the FDA-approved use of the PARP inhibitor olaparib is for ovarian or breast cancers in patients harboring a BRCA germline mutation [N Engl J Med 2012;366:1382–1392, N Eng J Med 2017;377:523–533]. Yet patients with tumors lacking BRCA loss of heterozygosity (LOH) or lacking other evidence of probable loss of normal BRCA gene product expression might be less likely to benefit from PARP inhibitor therapy, because the efficacy of PARP inhibitor therapy in patients with germline BRCA mutations would likely be predicated upon BRCA LOH in their tumors. Key Points Cancers in patients with germline mutations may be sporadic and unrelated to the germline mutation. Lynch syndrome is due to a germline mutated mismatch repair (MMR) gene. Cancers resulting from the germline MMR gene mutation as the predisposing event would be expected to be MMR deficient (dMMR) and microsatellite instability high (MSI-H). Sporadic cancers in patients with Lynch syndrome would be expected to be MMR proficient or microsatellite stable. Pembrolizumab is only approved for solid tumors demonstrating dMMR/MSI-H. Thus, whether the cancer tissue of origin is clearly associated with Lynch syndrome or not yet clearly established as a Lynch syndrome-related cancer (e.g., breast cancer), establishing the tumor to be dMMR/MSI-H is necessary to predict possible benefit and endorse the use of pembrolizumab. Ovarian cancers that develop in BRCA germline mutation carriers are so often related to the inherited mutated BRCA as the predisposing factor that testing the tumor for the footprint of BRCA-related ovarian cancer (BRCA loss of heterozygosity) is not necessary for use of the PARP inhibitor therapy olaparib. Future studies that include tumor evaluation for normal BRCA expression or surrogates of normal BRCA gene product expression might help determine which patients harboring a germline BRCA mutation are most likely to benefit from PARP inhibitor therapy.

Identification of effective targeted therapies for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) remains an unmet medical need. A patient with platinum‐refractory recurrent oral cavity HNSCC underwent comprehensive genomic profiling (CGP) that identified an activating MET mutation (R1004). The patient was treated with the oral MET tyrosine kinase inhibitor crizotinib with rapid response to treatment. Based on this index case, we determined the frequency of MET alterations in 1,637 HNSCC samples, which had been analyzed with hybrid capture‐based CGP performed in the routine course of clinical care. The specimens were sequenced to a median depth of >500× for all coding exons from 182 (version 1, n = 24), 236 (version 2, n = 326), or 315 (version 3, n = 1,287) cancer‐related genes, plus select introns from 14 (version 1), 19 (version 2), or 28 (version 3) genes frequently rearranged in cancer. We identified 13 HNSCC cases (0.79%) with MET alterations (4 point mutation events and 9 focal amplification events). MET‐mutant or amplified tumors represent a small but potentially actionable molecular subset of HNSCC. KEY POINTS. This case report is believed to be the first reported pan‐cancer case of a patient harboring a MET mutation at R1004 demonstrating a clinical response to crizotinib, in addition to the first documented case of head and neck squamous cell carcinoma (HNSCC) with any MET alteration responding to crizotinib. The positive response to MET inhibition in this patient highlights the significance of comprehensive genomic profiling in advanced metastatic HNSCC to identify actionable targetable molecular alterations as current treatment options are limited.