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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.

Patients with non-small cell lung cancer (NSCLC) containing ROS1 fusions can have a marked response to the ROS1-targeted tyrosine kinase inhibitors (TKIs), such as crizotinib. Common resistance mechanisms of ROS1-fusion targeted therapy are acquired mutations in ROS1. Along with the use of next-generation sequencing in the clinical management of patients with NSCLC during sequential targeted therapy, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Besides acquired resistance mutations, bypass mechanisms of resistance to epidermal growth factor receptor (EGFR)-TKI treatment are common in patients with EGFR mutations. Here we describe a patient with metastatic lung adenocarcinoma with CD74-ROS1 fusion who initially responded to crizotinib and then developed resistance by the acquired mutation of D1228N in the MET kinase domain, which showed short-term disease control for cabozantinib. Key Points The D1228N point mutation of MET is an acquired mutation for crizotinib resistance. The patient obtained short-term clinical benefit from cabozantinib therapy after resistance to crizotinib. The clinical use of next-generation sequencing could maximize the benefits of precision medicine in patients with cancer.

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.

BACKGROUND: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan‐ErbB family inhibitor that may be an effective treatment for NRG1 fusion‐driven tumors. PATIENTS AND METHODS: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion‐positive tumors treated with afatinib. RESULTS: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK‐NRG1 fusion and a KRAS mutation. Two patients received afatinib as first‐ or second‐line therapy, three patients received the drug as third‐ to fifth‐line therapy, and one patient received afatinib as fifteenth‐line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day. CONCLUSION: This report reviews previously published metastatic NRG1 fusion‐positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion‐positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion‐positive tumors. KEY POINTS: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan‐ErbB family inhibitor authorized for the treatment of advanced non‐small cell lung cancer that may be effective in NRG1 fusion‐driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion‐driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.

Precision oncology emphasizes genotyping as one of the mainstays of oncological decision‐making. The core information element exchanged between the laboratory and the oncologist is the precise mutation. Specifically, it is the written representation typically in the form of a variant description at the DNA or protein level. These annotations can be confusing, and many commercial laboratories have abandoned DNA‐level annotations. Here we present a complex double‐point mutation to illustrate a situation where a formally “correct” reporting nomenclature can obscure clinically relevant and potentially clinically actionable information. KEY POINTS: The Human Genome Variation Society (HGVS) currently recommends that “two variants separated by one or more nucleotides should be described individually and not as a combined ‘delins’ (deletion‐inserion).”. There remains confusion about the appropriate nomenclature to report variants and the significance of these variants among clinicians. It is the clinically integrated molecular‐genetic interpretation that will help clinicians make informed decisions to improve patient care.

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.

HER2 amplification, which results in overexpression of the receptor tyrosine kinase HER2, has been described in a wide variety of malignancies. HER2‐targeting agents have been incorporated into the treatment paradigms for HER2‐overexpressing breast and gastric cancer. More recently, these agents have shown promise in other gastrointestinal malignancies, such as colon cancer and biliary tract tumors. This study discusses two patients with gallbladder carcinoma and a third with ampullary carcinoma who were able to achieve marked responses to HER2‐directed therapy. These cases underscore the importance of molecular analysis for HER2 amplification/HER2 overexpression, irrespective of tumor histology, and highlight a need for further investigation of HER2‐directed therapy beyond breast and gastroesophageal cancers. KEY POINTS: Current guidelines recommend molecular assessment for HER2 overexpression exclusively in breast and gastric adenocarcinoma. The focus of this report is on three cases (two biliary tract and one ampullary carcinoma) in which amplification of HER2 or overexpression of HER2 was detected and treatment with HER2‐directed therapy resulted in robust responses. These cases exemplify responsiveness of non‐breast/gastric histologies to HER2‐directed therapies, highlighting several promising new settings for these agents. Testing for amplification of HER2 or overexpression of HER2 should be considered especially in rare diseases with limited treatment options.

Familial pancreatic adenocarcinoma (PDAC) is most commonly related to inheritance of a pathogenic BRCA variant (J Med Genet 2005;42:711–719). The National Comprehensive Cancer Network recommends germline testing for patients diagnosed with PDAC and recommends platinum‐based chemotherapy as the preferred initial systemic therapy for patients harboring a pathogenic BRCA germline variant with PDAC (https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455). PDACs related to pathogenic BRCA germline variants typically demonstrate BRCA loss of heterozygosity (LOH), which results in ineffective DNA damage repair due to a lack of normal BRCA gene product activity. By causing DNA damage, platinum‐based therapies have been shown to be highly effective therapies (Cancer Cell 2010;18:499–509, Gen Med 2015;17:569). In contrast, platinum‐based therapies would be predicted to be significantly less effective for PDACs in patients with pathogenic BRCA germline variants who have cancers that lack BRCA LOH. Poly (ADP‐ribose) polymerase 1 (PARP) is also key to effective DNA repair. The Food and Drug Administration has approved PARP inhibitors for patients carrying germline pathogenic BRCA variants and metastatic breast cancer or ovarian cancer (Ann Oncol 2019;30:558–566, J Clin Oncol 2015;33:244–250). PARP inhibitors would again be expected to be far less effective in patients who carry pathogenic BRCA germline variants with breast and ovarian cancers (those that lack BRCA LOH) than in those with BRCA‐related breast and ovarian cancers (which typically demonstrate BRCA LOH), because PARP is involved in DNA repair. Here, we present a patient harboring a pathogenic BRCA germline variant whose PDAC grew rapidly during platinum‐based therapy and lacked BRCA LOH and therefore was not likely BRCA related. Given the molecular fingerprint of BRCA‐related PDAC in patients with pathogenic BRCA germline variants and the mechanism of action of platinum‐based therapies and PARP inhibitors, this case underscores the importance of future studies aimed at determining whether the lack of BRCA LOH in PDACs in pathogenic BRCA germline variant carriers is a biomarker of less responsiveness to platinum‐based chemotherapy and PARP inhibitors. KEY POINTS: Platinum‐based therapy or Poly (ADP‐ribose) polymerase 1 (PARP) inhibitor therapies are highly effective systemic therapy options for most patients with pancreatic adenocarcinoma who carry a germline pathogenic BRCA variant. In the case presented here, a patient carrying a germline pathogenic BRCA variant saw rapid progression of his pancreatic adenocarcinoma while on platinum‐based therapy. Next‐generation sequencing confirmed that his pancreatic cancer was likely not related to BRCA loss of heterozygosity (LOH). Studies are needed to determine, in patients who harbor germline pathogenic BRCA variants, whether similar cancers (i.e., those that lack BRCA LOH) are less responsive to platinum‐based or PARP inhibitor therapies than are those more common BRCA‐related cancers (i.e., those that demonstrate LOH).

EGFR fusions are rare genomic events in non-small cell lung cancer (NSCLC), and a total of nine types have been previously reported in lung adenocarcinoma: EGFR-RAD51, EGFR-PURB, EGFR-ANXA2, EGFR-ZNF713, EGFR-YAP1, USP42-EGFR, EGFR-SEPTIN14, EGFR-TNS3, and EGFR-ZCCHC6. EGFR fusion mutations combined with EGFR amplification are even rarer in NSCLC. The EGFR-intergenic region (IGR) fusion mutation is unreported, and thus, there are no studies targeting this fusion together with EGFR amplification in lung adenocarcinoma. Our brief study provides clinical evidence that combined targeted therapy with gefitinib and cetuximab could result in a significant antitumor response in patients with the EGFR-IGR fusion and EGFR amplification. KEY POINTS: EGFR fusion mutations are rare, and EGFR fusion mutations combined with EGFR amplification are even rarer in non-small cell lung cancer (NSCLC). To the authors' knowledge, there is no previous report on the coexistence of the EGFR-intergenic region (IGR) fusion and EGFR amplification. This is the first report of a patient with NSCLC with the EGFR-IGR fusion and EGFR amplification who achieved a significant antitumor response from treatment with gefitinib combined with cetuximab.

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.

Herein, we report on a patient with known Lynch Syndrome and periampullary adenocarcinoma that exhibited a pathological complete response to neoadjuvant nivolumab plus ipilimumab. Two MSH2 mutations, high microsatellite instability (MSI-high), high tumor mutational burden (TMB) and elevated PD-L1 expression were identified by next-generation sequencing (NGS) and immunohistochemistry (IHC). Following FOLFIRINOX (Fluorouracil/Leucovorin/Irinotecan/Oxaliplatin) administration and disease progression, nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) were administered every 3 weeks for 4 total cycles. The patient responded well with minimal adverse effects and significant improvement in epigastric pain, appetite and body weight. She then underwent resection consisting of pancreaticoduodenectomy, which demonstrated pathological complete response. Complete genomic profiling of periampullary carcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma (PDAC) have different genetic profiles. This case provides an example of a patient who may have further benefited from first-line nivolumab plus ipilimumab to avoid the reduced efficacy and significant side effects associated with chemotherapy. KEY POINTS: A patient with known Lynch Syndrome and ampullary adenocarcinoma harboring two MSH2 mutations, high microsatellite instability (MSI-high), high tumor mutational burden (TMB) and elevated PD-L1 expression achieved pathological complete response with neoadjuvant nivolumab plus ipilimumab The combination of nivolumab plus ipilimumab may be a better first-line option for patients with ampullary adenocarcinomas harboring deficient mismatch repair (dMMR), MSI-high and high TMB Complete genomic profiling of periampullary adenocarcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma (PDAC) have different genetic profiles The presence of either MSI-high or high TMB could be an appropriate predictive biomarker for response to nivolumab plus ipilimumab in the context of Lynch Syndrome IMPLICATIONS FOR PRACTICE: This case provides an example of a patient with MSI-high and dMMR ampullary adenocarcinoma who may have benefited from first-line checkpoint inhibitor therapy, specifically with nivolumab plus ipilimumab. Comprehensive genomic profiling is beneficial in periampullary adenocarcinomas as it can identify tumors with specific genetic characteristics, like MSI-high, dMMR or high TMB that respond well to immune checkpoint inhibitors. When these characteristics are present and the goal of treatment is to facilitate downstage and prolong progression free survival, nivolumab plus ipilimumab should be considered, but trials in periampullary adenocarcinomas are required to confirm usage.

The addition of trastuzumab to chemotherapy regimen is the standard of care for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer; however, most patients eventually acquire trastuzumab resistance. Although some resistance mechanisms to trastuzumab-based regimens have been proposed, further understanding is required for developing therapeutic strategies to overcome the resistance. In the present work, we attempted to determine the possible resistance mechanism to trastuzumab in a patient with HER2-positive stage IV gastric adenocarcinoma. In this study, we first report the nucleotide change c.1899-1G>A at the intron 15 acceptor splice site promoting exon 16 deletion of HER2 as the potential mechanism of trastuzumab resistance in HER2-positive gastric adenocarcinoma. Key Points The combination of trastuzumab with chemotherapy is considered to be the standard therapy for HER2-positive advanced gastric cancer (GC), but most of the patients eventually acquire trastuzumab resistance. The mechanisms of resistance to trastuzumab in GC are poorly characterized. To the best of the authors' knowledge, this study is the first to implicate HER2 c.1899-1G>A, which results in exon 16 skpping, as the acquired resistance mechanism to trastuzumab in HER2-positive gastric adenocarcinoma. This work provides insights into the potential molecular mechanism of trastuzumab resistance, which is crucial in developing effective therapeutic strategies for HER2-positive GC patients refractory to trastuzumab.

The optimal management of advanced non-small cell lung cancer (NSCLC) with noncanonical epidermal growth factor receptor (EGFR) mutations (i.e., exon 19 deletion and exon 21 L858R) is constrained by the heterogeneous behavior of individual uncommon mutations and limited prospective clinical data in this setting. Despite encouraging results with osimertinib from a recently published phase II trial from South Korea, afatinib remains the only currently approved drug for patients with tumors harboring uncommon EGFR mutations (i.e., S768I, L861Q, and/or G719X). When used at the standard dose of 40 mg daily, afatinib is associated with significant rates of treatment-related adverse events, leading to frequent dose reductions and treatment discontinuations. We report a case of a woman with advanced NSCLC harboring EGFR-G719A mutation treated with afatinib (at an off-label pulse dose strategy that merits further evaluation in prospective studies) with sustained partial response for 20 months with manageable expected toxicities. Subsequent disease progression was mediated by off-target pan-EGFR inhibitor (including osimertinib)–resistant KRAS mutation and not by acquisition of EGFR-T790M. We further present the current state of evidence in the literature behind use of first-, second-, and third-generation tyrosine kinase inhibitors and summarize the evolving spectrum of activity ascribed to osimertinib (and newer EGFR inhibitors with a more favorable therapeutic window and intracranial penetration) in this population of patients with advanced NSCLC and uncommon EGFR mutations. Key Points Uncommon EGFR mutations characterize a heterogeneous group of patients with advanced non-small cell lung cancer (NSCLC). Afatinib is the only currently U.S. Food and Drug Administration–approved drug for management of advanced NSCLC with uncommon EGFR mutations (S768I, L861Q, and/or G719X). Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively. Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.

Alterations in c-MET, a tyrosine kinase receptor encoded by the MET gene, have been reported in approximately 3% of non-small cell lung cancer (NSCLC) cases and carry important treatment implications. The best studied genetic alterations are exon 14 skipping and gene amplification; however, gene rearrangement has also been described, and multiple fusion partners have been reported. Recently, in METex14-mutated NSCLC, multitarget tyrosine kinase inhibitors (TKIs), such as crizotinib and cabozantinib, as well as MET-selective TKIs, such as tepotinib and capmatinib, have demonstrated durable responses. In this study, we present the case of a 41-year-old woman with advanced NSCLC harboring an HLA-DRB1-MET gene fusion. The patient was offered successively two different MET multikinase inhibitors, crizotinib and cabozantinib, and the selective inhibitor tepotinib. Each time, including under tepotinib, the patient experienced rapid and complete responses associated with a tremendous improvement in her physical function. Key Points To our knowledge, this is the first report of a patient with non-small cell lung cancer harboring an HLA-DRB1-MET gene fusion demonstrating a clinical response to multiple MET inhibitors, including tepotinib. This finding illustrates the efficacy and rationale to targeting MET regardless of fusion partner and gives insight to pooling of patients with different MET fusion products in trials assessing safety and efficacy of novel molecules.

As an aggressive tumor, intrahepatic cholangiocarcinoma (ICC) originates in the epithelium of the bile duct and has a poor prognosis. The therapeutic options for ICC are challenging and limited because of poor response to chemotherapy and the lack of targeted therapy. Here we report on a 41-year-old female patient with ICC with EHBP1-MET fusion and multiple intrahepatic metastases responding to crizotinib. Next-generation sequencing–based tumor mutation profiling was performed on the tumor biopsy and circulating tumor DNA from plasma. A novel EHBP1-MET fusion was identified and confirmed by Sanger sequencing. Immunohistochemistry of biopsy sample also revealed c-MET positivity. Subsequently, the patient started treatment with MET inhibitor crizotinib. Magnetic resonance imaging scan demonstrated a partial response for 8 months. To the best of our knowledge, this is the first clinical case report of a patient with MET-rearranged ICC successfully treated with crizotinib. This case suggests that crizotinib may be a promising treatment option for patients with ICC with MET fusion, warranting further clinical investigation. Key Points To the authors' knowledge, this is the first reported case of EHBP1-MET fusion. This is also the first clinical case report of clinical benefit from crizotinib treatment in an intrahepatic cholangiocarcinoma (ICC) with MET fusion. MET fusion is rare in ICC, and inhibition of MET could be a viable option for ICC that warrants further clinical investigation.

Both metachronous and synchronous tumors pose a diagnostic and clinical challenge, more so when one of the specimens demonstrates the rare neuroendocrine histology. We describe a patient with sarcoidosis who was treated for endometrial and ovarian neoplasm, recurred with two separate histologies (adenocarcinoma and high grade neuroendocrine), both associated with microsatellite instability (MSI)-high status. Targeted next-generation sequencing of tumor with synonymous somatic alterations pointed to a common ancestry of all three tumors and patient was successfully treated with a tailored immunotherapy regimen. Her sarcoidosis worsened only slightly, and immunotherapy did not need to be discontinued. This case highlights the importance of molecular testing for the optimal therapy of complex synchronous tumors and the need for communication between surgical and medical oncologists in patients with MSI-high cancer. Key Points The case of a patient with a recurrent gynecological cancer presenting as microsatellite instability (MSI)-high endometrial adenocarcinoma and MSI-high neuroendocrine tumor is reported. This case demonstrated a common genetic lineage with good response to checkpoint inhibition without clinical worsening of autoimmune disease. This article adds to the literature, suggesting tumor evolution with neuroendocrine differentiation in some cancers, and argues that a molecular-based approach to treatment might achieve better understanding and possibly superior treatment outcomes.

Cancers of unknown primary (CUP) are histologically confirmed malignancies but for which further investigation cannot identify a primary site. Improvements in histopathologic modalities for diagnosis have lessened the frequency of CUPs to 3%–5% of all malignancies compared with historical estimates of 5%–10%. Despite this, there is an ongoing debate as to whether CUPs are malignancies where the primary is not found or if they are otherwise a fully separate entity. Improvements in molecular analysis holds promise for improved identification and treatment of CUPs with mixed preliminary results. Here we present a woman with CUP and metastases in her brain and lung. We performed genomic profiling to compare the molecular makeup of each site in order to establish treatment targets. Key Points Cancer of unknown primary remains a diagnostic and therapeutic challenge. Molecular analysis may provide improvements in diagnosis and novel treatment options. Different sites of metastatic disease have subtle variations in molecular profile. Sequencing of different sites may offer therapeutic options that are either already approved or available in clinical trial.

This article reports a case of advanced metastatic low-grade sarcoma. The patient was diagnosed with an inoperable large (14 × 12 cm) lesion on his neck in September 2015 and underwent two ineffective chemotherapies in the following 4 months. Interestingly, although several pathologists could not agree on the histopathological diagnosis, the precise molecular pathological diagnosis was obtained using next-generation sequencing (NGS) and finally brought excellent therapeutic effects. The patient was detected to have CARS-ALK fusion by NGS and then was successfully treated with crizotinib orally. He received surgical resection of primary and metastatic lesions after tumor shrinkage. The combined treatment brought a durable response for 40 months. Although the tumor recurred in July 2019, the patient has been responding well to the second-line ALK tyrosine kinase inhibitor alectinib to date. We performed whole genome sequencing on the patient's primary, metastatic, and recurrent tumors and did comprehensive genomic analysis. Furthermore, our analysis results revealed that a whole genome duplication event might have happened during tumorigenesis of this case. Key Points To our best knowledge, this is the first report of a very successful treatment with first- and second-line ALK tyrosine kinase inhibitors for CARS-ALK fusion–positive metastatic low-grade sarcoma. Molecular pathological result can guide precision treatment for sarcoma, even when the exact histopathology cannot be obtained. Multiple samples from this patient were analyzed using whole genome sequencing. Results provided detailed genomic characteristics and showed tumor evolution of this low-grade sarcoma case. A whole genome duplication event might have happened during tumorigenesis of this low-grade sarcoma case.

Here, we report a case of postoperative recurrence of gallbladder carcinoma (GBC) in a patient who declined systemic chemotherapy. ATM S1905Ifs*25 and STK11 K262Sfs*25 mutations were detected by next-generation sequencing. Oral administration of olaparib was initiated. One month later, the patient experienced relief of clinical symptoms, a decrease in CA19-9 level, and a reduction in abnormal signal in the subcapsular region. The tumor response remained stable for approximately 13 months. This is the first case to demonstrate the clinical benefits of olaparib treatment in a patient with GBC harboring an ATM-inactivating mutation. This observation helps to better inform treatment options to enhance the care of patients with advanced GBC. Key Points A patient with gallbladder carcinoma harboring an ATM-inactivating mutation responded to olaparib with a progression-free survival of 13 months. This is the first report that demonstrates the clinical benefits of olaparib treatment in a patient with gallbladder carcinoma with an ATM-inactivating mutation. It also highlights the importance of next-generation sequencing, which can provide valuable information for planning effective targeted therapies for gallbladder carcinoma. Evidence-based decisions help determine the best choice of treatment for individualized patient care.

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.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigms for a broad spectrum of malignancies. Because immune checkpoint inhibitors rely on immune reactivation to eliminate cancer cells, they can also lead to the loss of immune tolerance and result in a wide range of phenomena called immune-related adverse events (irAEs). At our institution, the management of irAEs is based on multidisciplinary input obtained at an irAE tumor board that facilitates expedited opinions from various specialties and allows for a more uniform approach to these patients. In this article, we describe a case of a patient with metastatic urothelial carcinoma who developed a maculopapular rash while being treated with a programmed death-ligand 1 inhibitor. We then describe the approach to management of dermatologic toxicities with ICIs based on the discussion at our irAE Tumor Board. Key Points Innocuous symptoms such as pruritis or a maculopapular rash may herald potentially fatal severe cutaneous adverse reactions (SCARs); therefore, close attention must be paid to the symptoms, history, and physical examination of all patients. Consultation with dermatology should be sought for patients with grade 3 or 4 toxicity or SCARs and prior to resumption of immune checkpoint inhibitors for patients with grade 3 or higher toxicity. A multidisciplinary immune-related adverse events (irAE) tumor board can facilitate timely input and expertise from various specialties, thereby ensuring a streamlined approach to management of irAEs.

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.

Cervical carcinosarcoma is an extremely rare type of neoplasm that lacks standard of care. Preclinical and clinical evidence has suggested that cryoablation in combination with immunotherapy may result in a synergistic effect, generating a more robust immune response to distant lesions. A few clinical trials have evaluated the efficacy of such combination treatment in a variety of solid tumors, but with conflicting results. This report describes the first clinical efficacy of cryoablation followed by pembrolizumab observed in a patient with tumor mutational burden (TMB)-high metastatic cervical carcinosarcoma that was negative for programmed cell death protein 1 expression, microsatellite instability stable, and had mutations in DNA polymerase epsilon (POLE). She had achieved complete response (CR) after 3 months of pembrolizumab treatment and had maintained CR as of the time of submission of this manuscript, with a progression-free survival of 11 months and counting. The case exhibited an exceptional response to cryoablation followed by pembrolizumab, potentially attributed to mutations in POLE, which lead to an extremely high TMB. This report paves the avenue for establishing treatment regimens for patients with TMB-high cervical carcinosarcoma. Key Points Owing to its rarity, cervical carcinosarcoma has not been well characterized, and currently, there is no standard of care for this disease. This report describes the first case of clinical efficacy of cryoablation followed by pembrolizumab observed in a patient with tumor mutational burden-high metastatic cervical carcinosarcoma. The case exhibited an exceptional response (maintained CR as of the time of submission of this article: 11 months) to cryoablation followed by pembrolizumab. This is the first POLE-mutated cervical carcinosarcoma case.

STK11 was first recognized as a tumor suppressor gene in the late 1990s based on linkage analysis of patients with Peutz-Jeghers syndrome. STK11 encodes LKB1, an intracellular serine-threonine kinase involved in cellular metabolism, cell polarization, regulation of apoptosis, and DNA damage response. Recurrent somatic loss-of-function mutations occur in multiple cancer types, most notably in 13% of lung adenocarcinomas. Recent reports indicate that KRAS-mutant non-small cell lung cancers harboring co-mutations in STK11 do not respond to PD-1 axis inhibitors. We present three patients with STK11-mutated tumors and discuss the proposed mechanisms by which germline and somatic alterations in STK11 promote carcinogenesis, potential approaches for therapeutic targeting, and the new data on resistance to immune checkpoint inhibitors. Key Points STK11 is a tumor suppressor gene, and loss-of-function mutations are oncogenic, due at least in part to loss of AMPK regulation of mTOR and HIF-1-α. Clinical trials are under way, offering hope to patients whose STK11-mutated tumors are refractory and/or have progressed on chemotherapeutic regimens. Whether gastrointestinal cancers with STK11 loss of function will show the same outcome and potential refractoriness to immune therapy that were reported for lung cancer is unknown. However, physicians managing such patients should consider the experience in lung cancer, particularly outside the context of a clinical trial. In the CheckMate-057 trial lung tumors harboring co-mutations in KRAS and STK11 had an inferior response to PD-1 axis inhibitors. Coupled with the observation that STK11-mutated tumors were found to have a cold immune microenvironment regardless of KRAS status, the conclusion could extend to KRAS wild-type tumors with STK11 mutation. Current data suggest that the use of PD-1 axis inhibitors may be ill advised in the presence of STK11 mutation.

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Growing evidence supports gene fusions as good candidates for molecularly targeted therapy in CRC. Here we describe a case of a 63-year-old man who had a radical right hemicolectomy procedure 24 months ago. Pathological diagnosis indicated colorectal adenocarcinoma with stage pT4N2bMx. During re-examination in December 2016, positron emission tomography/computed tomography scans indicated relapse with multiple lymph nodes metastasis. Then the patient received a nine-cycle combination treatment of XELOX and bevacizumab and showed progressive disease (PD). Subsequently, the patient was treated with bevacizumab plus FOLFIRI for 2 months before discontinuation because of adverse events. Paraffin sections of postoperative colorectal tissue were subjected to next-generation sequencing, and epidermal growth factor receptor (EGFR) amplification and rare EGFR–SEPT14 fusion were identified. The patient then received erlotinib, an EGFR tyrosine kinase inhibitor (TKI), and achieved a partial response. However, the patient subsequently showed PD, and a new variant, EGFRvIII, appeared in metastasis, which may be involved in erlotinib resistance. We suggest that there is value in treating patients harboring EGFR fusions with EGFR TKI therapy, and EGFR–SEPT14 fusion may be used as a therapeutic target for CRC. Key Points To the authors' knowledge, this is the first report of EGFR–SEPT14 fusion in colorectal cancer. The patient achieved a partial response after treatment with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. This report expands the list of gene fusions in colorectal cancer and highlights new targets for the therapeutic intervention. EGFRvIII may be involved in erlotinib resistance, which is rare in colorectal cancer.

Combined MEK-BRAF inhibition is a well-established treatment strategy in BRAF-mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF-MEK inhibitor treatment are unavailable. Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient. Key Points BRAF mutations constitute an attractive druggable target in multiple myeloma. This is the first genomic dissection of the central nervous system involvement in a multiple myeloma patient harboring a druggable BRAFV600E mutation. Deep genomic characterization of the extramedullary lesion prompted a personalized therapeutic approach. Acquisition of CIC mutation confers a mechanism of BRAF-MEK inhibitor drug resistance in multiple myeloma. The in silico interrogation of the CoMMpass clinical study revealed 10 patients with somatic mutations of CIC and its downregulation at gene expression level in multiple myeloma. CIC gene silencing decreases the sensitivity of multiple myeloma cells to BRAF-MEK inhibition in vitro. The correlation between CIC downregulation and ETV4/5 nuclear factor expression in multiple myeloma BRAF-mutant cells is shown for the first time. CIC mutation, its downregulation, and the related downstream effect on MMP24 support disseminative potential providing new clues in the extramedullary biology definition.