Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study.

BACKGROUND: Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study. METHODS: A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS). RESULTS: Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0-15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R2 = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01-10.83), P = 0.048], PFS [HR 0.55 (0.28-1.07), P = 0.08], and OS [HR 0.42 (0.21-0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups. CONCLUSIONS: Personalized combination therapies targeting a majority of a patient's molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies. TRIAL REGISTRATION: I-PREDICT ( NCT02534675 ) was registered on August 25, 2015.

Overall and cancer-specific survival of patients with breast, colon, kidney, and lung cancers with and without chronic lymphocytic leukemia: a SEER population-based study.

PURPOSE: Chronic lymphocytic leukemia (CLL) is associated with an increased risk of developing second cancers. However, it is unknown whether CLL alters the disease course of these cancers once they occur. PATIENTS AND METHODS: All patients with cancers of the breast (n = 579,164), colorectum (n = 412,366), prostate (n = 631,616), lung (n = 489,053), kidney (n = 95,795), pancreas (n = 82,116), and ovary (n = 61,937) reported to the SEER program from 1990 to 2007 were identified. Overall survival (OS; death resulting from any cause) and cancer-specific survival were examined, comparing patients with and without pre-existing CLL. Cancer-specific survival was evaluated for each tumor type in a site-specific manner (eg, death resulting from breast cancer in a patient with breast cancer). RESULTS: Patients with cancers of the breast (hazard ratio [HR], 1.70; P < .001), colorectum (HR, 1.65; P < .001), kidney (HR, 1.54; P < .001), prostate (HR, 1.92; P < .001), or lung (HR, 1.19; P < .001) had inferior OS if they had a pre-existing diagnosis of CLL after adjusting for age, sex, race, and disease stage. These results for OS remained significant for patients with cancers of the breast, colorectum, and prostate after excluding or censoring CLL-related deaths. Cancer-specific survival was also inferior for patients with cancers of the breast (HR, 1.41; P = .005) and colorectum (HR, 1.46; P < .001) who had pre-existing CLL after adjusting for age, sex, race, and disease stage. CONCLUSION: Inferior OS and cancer-specific survival was observed for several common cancers in patients with pre-existing CLL. Additional studies are needed to determine the optimal management of these malignancies in patients with CLL and whether more aggressive screening or alternative approaches to adjuvant therapy are needed.

Neuroleukemiosis: an unusual cause of peripheral neuropathy.

Leukemia may initially present as a peripheral neuropathy, leading to a delay in diagnosis. Leukemic infiltration of peripheral nerves, or neuroleukemiosis (NL), is exceedingly rare, with no established diagnostic or therapeutic guidelines. Five cases are presented. All patients were men with a median age of 68 years (range 46-72). Three patients had acute myeloid leukemia (AML) and two had chronic lymphocytic leukemia (CLL). In two patients, leukemia presented with peripheral nerve involvement and both were found to have positive cerebrospinal fluid (CSF) cytology, making the diagnosis AML, despite negative bone marrow and peripheral smear. All patients had painful, progressive, motor and sensory deficits. Clinical patterns were mononeuropathy (n =1), multiple mononeuropathies (n =1) and plexopathy (n =3). Magnetic resonance imaging (MRI) detected mass lesions in 4/5 cases, with avid fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) useful in all of these for following clinical disease progression. Three cases of nerve biopsy were performed, two of which were diagnostic of leukemic infiltration. Radiation treatment rapidly relieved pain in patients with mass lesions, in combination with chemotherapy. Four patients had disease relapse, four systemic and one also in peripheral nerves. These cases are discussed in the context of the broader literature.

Epidermal growth factor receptor (EGFR) inhibitor-induced rash: a consecutive patient series that illustrates the need for rigorous palliative trials.

PURPOSE: Rash is the most common side effect of epidermal growth factor receptor (EGFR) inhibitors and negatively impacts quality of life. This single-institution study sought to explore how rash is currently managed outside a clinical trial setting and to further characterize general clinical aspects of this rash. METHODS/RESULTS: Among 4101 consecutive patients with cancer of the lung, colorectum, pancreas, and head and neck, 138 had received an EGFR inhibitor. Within this group, 96 (69%) developed a rash. Forty-nine of these patients were prescribed rash therapy, and a total of 26 different palliative regimens were used. Surprisingly, most patients, with the exception of 2, appear to have manifested evidence of rash improvement-even when unproven or disproved therapies had been prescribed. Fourteen patients stopped their EGFR inhibitor because of rash, and 11 were then able to restart. No demographic variables were able to predict rash development. CONCLUSION: The observation that multiple, largely unproven, anecdotal therapies are being prescribed to palliate EGFR inhibitor-induced rashes underscores the need for more rigorous, prospective palliative trials.

Rash from EGFR inhibitors: opportunities and challenges for palliation.

The epidermal growth factor receptor (EGFR) inhibitors represent a relatively new class of cancer agents that also provide new challenging side effects for cancer patients. This article reviews the clinical aspects of EGFR inhibitor-induced rash, which occurs most commonly with use of these agents, and discusses some of the challenges faced in attempting palliation treatment.