Oral Premalignant and Malignant Lesions in Fanconi Anemia Patients.

OBJECTIVE: There is a lack of data supporting cancer surveillance in pediatric Fanconi Anemia patients. We sought to describe the rates of upper aerodigestive lesions and malignancy in this population to augment current management guidelines. METHODS: A retrospective cohort study of patients with Fanconi Anemia from a quaternary referral center between 2007-2021 was completed for head and neck cancer risk. RESULTS: One hundred and five FA patients were reviewed. Average age at presentation was 11.3 years old and 90.5% of patients underwent hematopoietic stem cell transplant (HSCT). A total of 8.6% of patients had leukoplakia or erythroplakia and 3.8% developed malignancy. The standardized incidence ratio of head and neck malignancy was 483.8. Patients presented with leukoplakia and malignancy at an average age of 14.6 and 25.1 years old, respectively. Malignancies were aggressive and marked by recurrence. There were no premalignant or malignant lesions found on flexible laryngoscopy. This series represents the largest longitudinal series of pediatric FA head and neck lesions. CONCLUSIONS: Fanconi Anemia patients should begin screening for head and neck cancer at age 10 or after HSCT. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 133:1745-1748, 2023.

Characterization of Fanconi Anemia Patients with Head and Neck Squamous Cell Carcinoma: Israel Fanconi Registry.

BACKGROUND: Recent studies show a high risk of developing malignancy in patients with Fanconi anemia. The most common solid tumor in this condition is head and neck squamous cell carcinoma (HNSCC) and there is often uncertainty and about disease behavior as well as chemotherapy and radiation response. OBJECTIVES: To describe and characterize HNSCC among Fanconi anemia patients on the Israeli Fanconi Registry. METHODS: Our study population included patients in Israel's inherited bone marrow failure registry who were diagnosed with Fanconi anemia between1980 and 2016. Demographic, clinical, and laboratory data were collected from patient charts. RESULTS: From the collected data, HNSCC was confirmed in 6/111 (5.4%) Fanconi anemia patients; 1 (17%) had classic HNSCC risk factors of tobacco abuse and 4 (56%) had undergone primary surgery. The 3 (50%) receiving concurrent chemoradiotherapy had mild side effects, while half developed metachronous primary malignancy, and all developed > 2 primary malignancies. The overall median survival of the patients in our study was 14 (0.5-57) months. CONCLUSIONS: Fanconi anemia patients have a very high risk of developing HNSCC. Proactive screening for malignancies is needed for the head and neck regions. We also found that chemoradiotherapy can be used safely in high-stage cancers.

Fanconi anemia: current insights regarding epidemiology, cancer, and DNA repair.

Fanconi anemia is a genetic disorder that is characterized by bone marrow failure, as well as a predisposition to malignancies including leukemia and squamous cell carcinoma (SCC). At least 22 genes are associated with Fanconi anemia, constituting the Fanconi anemia DNA repair pathway. This pathway coordinates multiple processes and proteins to facilitate the repair of DNA adducts including interstrand crosslinks (ICLs) that are generated by environmental carcinogens, chemotherapeutic crosslinkers, and metabolic products of alcohol. ICLs can interfere with DNA transactions, including replication and transcription. If not properly removed and repaired, ICLs cause DNA breaks and lead to genomic instability, a hallmark of cancer. In this review, we will discuss the genetic and phenotypic characteristics of Fanconi anemia, the epidemiology of the disease, and associated cancer risk. The sources of ICLs and the role of ICL-inducing chemotherapeutic agents will also be discussed. Finally, we will review the detailed mechanisms of ICL repair via the Fanconi anemia DNA repair pathway, highlighting critical regulatory processes. Together, the information in this review will underscore important contributions to Fanconi anemia research in the past two decades.

The incidence and spectrum of congenital hand differences in patients with Fanconi anaemia: analysis of 48 patients.

We analysed the spectrum of congenital hand differences in a cohort of patients with Fanconi anaemia (FA). Data of 48 FA patients at the National Cancer Institute were reviewed focusing on age at diagnosis, type and severity of limb difference and any potential association with other known clinical anomalies that are part of the FA phenotype, specifically VACTERL-H and PHENOS. Twenty-eight patients had an upper limb difference, which always included thumb hypoplasia. Twenty-three patients had bilateral upper limb differences, including varying combinations and severities of thumb hypoplasia, radial dysplasia and thumb duplication. Patients with a limb difference were diagnosed at a younger age (<2 years: 15/28 with limb anomaly versus 4/20 without a limb anomaly). However, 7/28 with limb anomalies, usually thumb hypoplasia, were not diagnosed until after 6 years of age. This study demonstrates the broad spectrum of radial ray anomalies within the FA phenotype along with the possibility of either unilateral or bilateral upper limb differences and adds further merit to consideration of screening for FA in all cases of radial ray anomaly.Level of evidence: II.

Cancer in Children With Fanconi Anemia and Ataxia-Telangiectasia-A Nationwide Register-Based Cohort Study in Germany.

PURPOSE: Fanconi anemia (FA) and ataxia-telangiectasia (AT) are rare inherited syndromes characterized by abnormal DNA damage response and caused by pathogenic variants in key DNA repair proteins that are also relevant in the pathogenesis of breast cancer and other cancer types. The risk of cancer in children with these diseases is poorly understood and has never been assessed in a population-based cohort before. METHODS: We identified 421 patients with FA and 160 patients with AT diagnosed between 1973 and 2020 through German DNA repair disorder reference laboratories. We linked patients' laboratory data with childhood cancer data from the German Childhood Cancer Registry. RESULTS: Among 421 patients with FA, we observed 33 cases of childhood cancer (15 cases of myelodysplastic syndrome; seven cases of acute myeloid leukemia; two cases of lymphoma, carcinoma, medulloblastoma, and nephroblastoma, respectively; and one case of rhabdomyosarcoma, acute lymphoblastic leukemia, and glioma, respectively) versus 0.74 expected (on the basis of population-based incidence rates in Germany). This corresponds to a 39-fold increased risk (standardized incidence ratio [SIR] = 39; 95% CI, 26 to 56). For all FA subgroups combined, the cancer-specific SIR for myeloid neoplasms was 445 (95% CI, 272 to 687). Among the 160 patients with AT, we observed 19 cases of childhood cancer (15 cases of lymphoma, three cases of leukemia, and one case of medulloblastoma) versus 0.32 expected. This corresponds to a 56-fold increased risk (SIR = 56; 95% CI, 33 to 88). The cancer-specific SIR for Hodgkin lymphoma was 215 (95% CI, 58 to 549) and for non-Hodgkin lymphoma 470 (95% CI, 225 to 865). CONCLUSION: Approximately 11% of patients with FA and 14% of patients with AT develop cancer by age 18 years.

Risk of cancer in heterozygous relatives of patients with Fanconi anemia.

PURPOSE: Fanconi anemia (FA) is a cancer-prone inherited bone marrow failure syndrome caused by biallelic pathogenic variants in one of >22 genes in the FA/BRCA DNA repair pathway. A major concern is whether the risk of cancer is increased in individuals with a single pathogenic FA gene variant. METHODS: We evaluated the risk of cancer in the relatives of patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome cohort. We genotyped all available relatives and determined the rates, types of cancer and the age of patients at cancer diagnosis. We calculated the observed-to-expected (O/E) cancer ratios using data from the Surveillance, Epidemiology, and End Results Program adjusted for age, sex, and birth cohort. RESULTS: The risk of cancer was not increased among all FA relatives and FA heterozygotes (O/E ratios of 0.78 and 0.79, respectively). In particular, the risk of cancer was not increased among FANCA or FANCC heterozygotes (O/E ratios of 0.92 and 0.71, respectively). Relatives did not have typical FA cancers, and age at cancer diagnosis was not younger than expected. CONCLUSION: Understanding the risk of cancer in individuals with single pathogenic FA variants is critical for counseling and management. We did not find increased risk of cancer in these individuals. These findings do not extend to the known cancer predisposition autosomal dominant FA genes, namely BRCA1, BRCA2, PALB2, BRIP1, and RAD51C.

Kidney complications in 107 Fanconi anemia patients submitted to hematopoietic cell transplantation.

Fanconi anemia (FA) is a rare disease characterized by progressive bone marrow failure, cancer predisposition, and multiple systemic malformations, including congenital abnormalities of the kidney and urinary tract (CAKUT). Hematopoietic cell transplantation (HCT), the only potentially curative treatment for the hematological complications of FA, may precipitate acute kidney injury (AKI) and hypertension. We retrospectively investigated 107 FA patients who underwent HCT between 2009 and 2017. We investigated the incidence and risk factors of AKI within 100 days after HCT in a cohort of FA patients, and kidney function and hypertension over 2-year follow-up.The incidence of AKI (mainly stage I) was 18.7%. Patients aged ≥ 11 years at transplantation showed a higher risk of AKI (OR 3.53). The eGFR was 60-90 mL/min/1.73 m2 in 53 (49.5%), 55 (51.4%), 50 (50.5%), 50 (51%), and 46 (59.7%) patients before HCT, at 100 days, 6 months, 1 year, and 2 years. Within the first 100 days after HCT, hypertension was observed in 72% of the patients and was associated with cyclosporine therapy. Most (62.3%) patients had stage 2 hypertension. CAKUT was observed in 33.7% of the patients and was associated with both hypertension (86%) and diminished kidney function but not with AKI.Conlusion: Although AKI, a commonly known HCT complication, was mild in this study, the prevalence of chronic kidney disease (CKD), as well as the high incidence of hypertension, specially associated with CAKUT point out the importance of kidney care in short and long-term follow up of FA patients. What is Known: • Fanconi anemia (FA) is the most frequent inherited bone marrow failure in children, and 30% of cases have congenital anomalies of kidney (CAKUT). • Acute kidney injury and hypertension after hematopoietic cell transplantation (HCT) may impact the outcomes.. What is New: • Despite the presence of CAKUT and stage 2 CKD in 33.7% and 50% of the patients, respectively, AKI was mild and transitory after HCT in FA patients. • CAKUT in FA patients was associated with lower kidney function and hypertension after HCT.

Cutaneous findings in Fanconi anemia.

BACKGROUND: Fanconi anemia (FA) is a genetic disorder that results in bone marrow failure, physical abnormalities, and solid organ malignancies. The diagnosis of FA is often delayed because the early disease characteristics have not been well established. OBJECTIVE: To outline the spectrum of cutaneous findings seen in patients with FA. METHODS: A cross-sectional study in which patients with FA received a full-body skin examination. Patient characteristics are summarized with mean (SD) for continuous and count (%) for categorical variables. Poisson regression and logistic regression models were used to examine the relationships between pigmentary changes and patient characteristics. RESULTS: At least 1 cutaneous pigmentary alteration was present in 96.8% of patients, most arising before the teenage years. The most common finding was café-au-lait macules. Other findings included hypopigmented macules, skin-fold freckle-like macules, extensive sun-exposed freckling, and both hypopigmented and hyperpigmented pigment macules. LIMITATIONS: Patients received a single assessment, so the number of pigmentary changes could not be assessed over time. CONCLUSIONS: Characteristic morphology of FA includes faint and ill-defined café-au-lait macules, hypopigmented skin-fold freckle-like macules and the concurrence of hypopigmented and hyperpigmented macules. The recognition of these findings could aid clinicians in making earlier diagnoses.

Clinical and Genetic Features of Patients With Fanconi Anemia in Lebanon and Report on Novel Mutations in the FANCA and FANCG Genes.

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome and presents with cytopenias, characteristic physical features, increased chromosomal breaks, and a higher risk of malignancy. Genetic features of this disease vary among different ethnic groups. We aimed to identify the incidence, outcome, overall condition, and genetic features of patients affected with FA in Lebanon to optimize management, identify the most common genes, describe new mutations, and offer prenatal diagnosis and counseling to the affected families. Over a period of 17 years, 40 patients with FA were identified in 2 major diagnostic laboratories in Lebanon. Information was obtained on their clinical course and outcome from their primary physician. DNA was available in 20 patients and was studied for underlying mutations. FANCA seemed to be the most frequent genetic alteration and 2 novel mutations, one each in FANCA and FANCG, were identified. Nine patients developed various malignancies and died. This is the first study looking at clinical and genetic features of FA in Lebanon, and points to the need for establishing a national and regional registry for this condition.

Screening of the FANCA gene mutational hotspots in the Pakistani fanconi anemia patients revealed 19 sequence variations.

Fanconi anemia (FA) is a recessive disorder that predispose to bone marrow failure and multiple congenital anomalies in affected individuals worldwide. To date, 22 FA genes are known to harbor sequence variations in disease phenotype. Among these, mutations in the FANCA gene are associated with 60% to 70% of FA cases. The aim of the present study was to screen FA cases belonging to consanguineous Pakistani families for selected exons of FANCA gene which are known mutational hotspots for Asian populations. Blood samples were collected from 20 FA cases and 20 controls. RNA was extracted and cDNA was synthesized from blood samples of cases. DNA was extracted from blood samples of cases and ethnically matched healthy controls. Sanger's sequencing of the nine selected exons of FANCA gene in FA cases revealed 19 genetic alterations of which 15 were single nucleotide variants, three were insertions and one was microdeletion. Of the total 19 sequence changes, 13 were novel and six were previously reported. All identified variants were evaluated by computational programs including SIFT, PolyPhen-2 and Mutation taster. Seven out of 20 analyzed patients were carrying homozygous novel sequence variations, predicted to be associated with FA. These disease associated novel variants were not detected in ethnically matched controls and depict genetic heterogeneity of disease.

A founder variant in the South Asian population leads to a high prevalence of FANCL Fanconi anemia cases in India.

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, predisposition to cancer, and congenital abnormalities. FA is caused by pathogenic variants in any of 22 genes involved in the DNA repair pathway responsible for removing interstrand crosslinks. FANCL, an E3 ubiquitin ligase, is an integral component of the pathway, but patients affected by disease-causing FANCL variants are rare, with only nine cases reported worldwide. We report here a FANCL founder variant, anticipated to be synonymous, c.1092G>A;p.K364=, but demonstrated to induce aberrant splicing, c.1021_1092del;p.W341_K364del, that accounts for the onset of FA in 13 cases from South Asia, 12 from India and one from Pakistan. We comprehensively illustrate the pathogenic nature of the variant, provide evidence for a founder effect, and propose including this variant in genetic screening of suspected FA patients in India and Pakistan, as well as those with ancestry from these regions of South Asia.

Two enemies, one fight: An update of oral cancer in patients with Fanconi anemia.

Fanconi anemia (FA) is a rare inherited genetic condition that may lead to bone marrow failure, leukemia, and/or solid tumors. It is caused by the loss of function of at least 1 gene of the FA/BRCA pathway, which is necessary for DNA repair. Patients with FA have a 200-fold to 1000-fold risk of developing head and neck cancer, mainly oral squamous cell carcinoma (OSCC), and of doing so at a much younger age than individuals within the general population. Also, patients who have FA with OSCC have poor overall survival rates, reinforcing the necessity to detect OSCC early. The scope of the current review is to provide an update on OSCC in patients with FA.

Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients.

Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known FANC genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FANC genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. FANCA and FANCG pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one FANCA and two FANCG hot spot mutations, which are found at low percentages (0.04-0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). FANCB was the third most common complementation group and only one FANCC case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing FANC gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.

Treatment modalities and outcomes of Fanconi anemia patients with head and neck squamous cell carcinoma: Series of 9 cases and review of the literature.

BACKGROUND: Fanconi anemia (FA) is associated with an increased risk of developing head and neck squamous cell cancer (HNSCC) and presents a treatment dilemma due to concerns of increased toxicities from chemotherapy and radiation therapy (RT). METHODS: We reviewed the literature on HNSCC in FA patients and report on our experience treating 9 FA patients with HNSCC. RESULTS: Surgery was generally well-tolerated and surgery alone resulted in durable local control for 2 patients. Four patients received adjuvant RT that was tolerable in most cases, although 1 patient required a treatment break and early cessation of RT. Three of the irradiated patients received concurrent cetuximab. CONCLUSIONS: In patients with adverse features, adjuvant radiation with concurrent cetuximab may be feasible with careful monitoring, although local disease control is infrequent. Early detection via screening permitting a surgery-alone approach represents the best opportunity for cure in FA patients with HSNCC.

A Global MicroRNA Profile in Fanconi Anemia: A Pilot Study.

PURPOSE: Fanconi anemia (FA) is a complex tumor-prone disease defined by an entangled genotype and phenotype. Despite enormous efforts in the last 20 years, a comprehensive and integrated view of the disease is still missing. The aim of this pilot study was to establish whether a global microRNA (miRNA) analysis approach could be helpful in defining aspects in FA phenotype, which might deserve future attention with the perspective to develop miRNA-based therapies. METHODS: miRNA array were employed to characterize the global miRNA (miRNoma) profile of FA RNA samples with respect to normal samples. RESULTS: We report and compare miRNA profile from two FA established cell lines and three FA patients. This analysis reveals that 36 and 64 miRNAs, respectively, are found differentially expressed (>2-fold variation and P < 0.05) in the samples from FA cell lines and FA patients. Overlap of these data results in 24 miRNAs as shared in the two sample populations. Available bioinformatics methods were used to predict target genes for the differentially expressed miRNAs and to perform pathway enrichment analysis. CONCLUSIONS: Seven pathway results associated with the FA phenotype. It is interesting to note that some of these pathways were previously unrelated to FA phenotype. It might be important to focus on these pathways not previously emerged as dysfunctional in FA to better define the pathophysiological context of this disease. This is the first report of a global miRNA analysis in FA.

Endoscopic findings and esophageal cancer incidence among Fanconi Anemia patients participating in an endoscopic surveillance program.

BACKGROUND AND AIMS: The primary clinical characteristics of Fanconi Anemia (FA) include typical physical features, progressive bone marrow failure, and an increased incidence of neoplasms, including esophageal carcinoma. Currently, there are no data regarding endoscopic findings or the interval time to malignancy in these patients. Data about the contribution of Human Papilloma Virus (HPV) to esophageal carcinoma is conflicting. Our objective is to document the upper gastrointestinal (GI) findings at baseline, document cancer incidence, and evaluate the role of HPV among these cancers. METHODS: We reviewed endoscopic and clinical data of FA subjects who participated in active surveillance before cancer diagnosis. Incident esophageal cancers were stained for HPV p16 protein. RESULTS: Eight FA patients were included (men 62.5%; median age at first endoscopy 20 years, median endoscopies number: 5.5). At baseline, 8/8 had endoscopic evidence for reflux esophagitis. In 3/8 the reflux esophagitis was mild and in 5/8 it was moderate or severe. During the follow up time (median time 4.5 years 2/8 developed Barrett's esophagus and 2/8 patients had incident esophageal squamous cell carcinoma during follow up, at intervals of eight and eighteen months from the previous upper endoscopy. Both cancers stained negative for HPV P16. CONCLUSIONS: FA subjects have both an extremely high risk for esophageal cancer within short intervals and a very high prevalence of reflux esophagitis with various severities. Active surveillance programs in specialized centers including annual upper endoscopies should be considered in these patients.

Fanconi anaemia in South Africa: Past, present and future.

Fanconi anaemia (FA) is an inherited genetic disorder characterised by somatic anomalies, bone marrow failure and an increased predisposition to solid tumours and haematological malignancies. South African (SA) black and Afrikaner individuals are at higher than average risk for this condition owing to genetic founder mutations in certain Fanconi-associated genes. This review explores the epidemiology, clinical presentation, diagnostic modalities and recommended care of affected patients, focusing on the founder population groups in SA. The early diagnosis of FA is important and provides improved opportunities for early intervention, but remains challenging.

Incidence of Fanconi anaemia in phenotypically normal aplastic anaemia patients in West Bengal.

OBJECTIVES: Fanconi anaemia (FA) is a rare inherited bone marrow failure and autosomal recessive blood disorder. FA patients have a higher risk of cancer, including acute myeloid leukaemia and squamous cell carcinoma. Maximum, but not all, affected individuals have one or more somatic abnormalities, including skin, skeletal, genitourinary, gastrointestinal, cardiac and neurological anomalies, etc. Positive stress cytogenetics has immense implications for the treatment and management of FA. The aim of our study was to find out the incidence of FA in the population of phenotypically normal aplastic anaemia (AA) patients in West Bengal. METHODS: Ethical clearances were obtained from the corresponding institutional committees. A total of 117 AA cases was selected. Stress cytogenetics was performed from peripheral venous blood (PVB) samples of 63 AA patients (age ≤ 50 years) and 63 age- and sex-matched healthy individual (control) using Mitomycin C (MMC). RESULTS: Out of 63 AA patients, 6 (9.25%) cases showed positive stress cytogenetics suggestive of FA, which is statistically significant (p-value - 0.000532), analysed by chi-square test. DISCUSSION: A considerable percentage of patients showing sensitivity towards MMC, even if they are phenotypically normal and did not have any distinguishable features which are generally found in FA. CONCLUSION: This observation may indicate that stress cytogenetics analysis of phenotypically normal AA patients (≤50 years) is essential for the improvement of the treatment procedure.

Analysis of FANCC gene mutations (IVS4+4A>T, del322G, and R548X)in patients with Fanconi anemia in Pakistan.

BACKGROUND/AIM: Fanconi anemia (FA) is an autosomal recessive disease determined by mutations in at least 16 genes, with distinct distributions in different populations. To the best of our knowledge, there are no reports regarding the molecular basis of the disease in FA patients in Pakistan. The current study aimed to determine the frequency of FANCC gene mutations, i.e. IVS4+4A>T, del322G, and R548X, in FA patients. MATERIALS AND METHODS: Genomic DNA was obtained from 36 FA patients. All samples were analyzed by polymerase chain reaction and restriction fragment length polymorphism techniques. RESULTS: Mutation IVS4+4A>T was identified in 26 (72.2%) patients. It was homozygous in 6 and heterozygous in 20 patients. Del322G and R548X were found with the following prevalences: del322G, 5.6%, and R548X, 5.6%. Patients with these two mutations were compound heterozygotes having concomitant IVS4+4A>T mutation. CONCLUSION: These results suggest that mutation IVS4+4A>T is the most prevalent mutation in our group of patients. This analysis of Pakistani patients also suggests that there is no significant difference between IVS4+4A>T homozygotes and the rest of the patients with regard to severity of clinical phenotype.

Systematic review and individual patient data analysis of pediatric head and neck squamous cell carcinoma: An analysis of 217 cases.

INTRODUCTION: Pediatric head and neck Squamous cell carcinoma (PHNSCC) is a rare disease. The optimum treatment and outcome remains poorly understood because of rarity. METHODS: We conducted an individual patient data analysis of PHNSCC. Two authors independently searched PubMed, google search, and Cochrane library for eligible studies using following search words: Pediatric Head and neck squamous cell carcinoma, Head and neck squamous cell carcinoma under age of 20, Head and neck squamous cell carcinoma in young, PHNSCC till June 1, 2016 published in English language. RESULTS: Total of 217 patients of PHNSCC were found in the literature. Median age among the cohort was 15 years (Range: 0-20 years) with a clear male preponderance. Oral cavity tumors were commonest 75 (70%) followed by laryngeal neoplasms 16(15%). Median disease free survival was 9 months (Range: 0-216 months). Median overall survival was 48 months (Range: 1-216 months). In univariate analysis treatment modality had significant impact on disease free survival (DFS). Whereas, patients treated with Surgery, Laryngeal primary had significantly better OS. Patients with associated fanconis anemia had significantly worse overall survival (OS). CONCLUSION: PHNSCC is a rare disease with poorer outcome. Associated DNA defects leads to poorer OS. Patients treated with surgery alone or surgery followed by adjuvant radiation had better DFS and OS. Molecular profiling and personalized therapy may improve survival with limited toxicity.