Multicenter Real-World Data of Subsequent Chemotherapy after Progression to PARP Inhibitors in a Maintenance Relapse Setting.

Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included [46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes]. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval [PFI] was >6 months after the last cycle of prior platinum) [median PFI 12.0 months (interquartile range, IQR, 8.8−17.1)]. Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6−9.2), and median OS (mOS) of 20.6 months (95% CI 13.6−28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 [IQR11.2−22.2] and 10.3 [IQR 7.4−14.9] months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5−8.6) versus 7.5 months (95% CI 6.5−10.1, p = 0.03), and 16.4 (95% CI 9.3−27.5) versus 24.2 months (95% CI 17.2−NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients.

Prospective Biomarker Study in Advanced RAS Wild-Type Colorectal Cancer: POSIBA Trial (GEMCAD 10-02).

BACKGROUND: RAS testing is used to select patients with anti-epidermal growth factor receptor (EGFR) therapies sensitivity in metastatic colorectal cancer (mCRC). However, other biomarkers such as BRAF, PIK3CA/PTEN, and p-IGF-1R+/MMP7+ (double positive [DP] phenotype) have not been prospectively assessed to predict anti-EGFR resistance. MATERIALS AND METHODS: We designed a multicenter prospective trial (NCT01276379) to evaluate whether the biomarkers BRAF mutation, PIK3CA mutation/PTEN loss, and DP phenotype can improve the prediction for 12-months progression-free survival (PFS) over the use of clinical variables exclusively in patients with RAS wild-type (WT) mCRC treated with standard chemotherapy plus biweekly cetuximab as first-line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12-month PFS based on the analysis of clinical and selected biomarkers (α = .05, ß = .2). The discriminatory capacity of the biomarkers was evaluated using receiver operating characteristic curves. RESULTS: We included 181 RAS WT patients. The biomarker distribution was as follows: BRAF mutant, 20 patients (11%); PIK3CA mutated/PTEN loss, 98 patients (58%); DP, 23 patients (12.7%). The clinical variables in the clinical score were progression status >0, left-sided tumor, and resectable liver metastasis as the only metastatic site. The area under the curve (AUC) of the score containing the clinical variables was 0.67 (95% confidence interval [CI], 0.60-0.75). The AUC of the score with clinical variables and BRAF mutational status was 0.68 (0.61-0.75, p = .37). The AUC of the score with clinical variables and PI3KCA mutation/PTEN status was 0.69 (0.61-0.76, p = .32). The AUC of the score with clinical variables and DP phenotype was 0.66 (0.58-0.73, p = .09). CONCLUSION: The addition of BRAF, PIK3CA/PTEN, and DP to a clinical score does not improve the discrimination of 12-month PFS. IMPLICATIONS FOR PRACTICE: This prospective biomarker design study has important clinical implications because many prospective clinical trials are designed with the hypothesis that BRAF mutation per se and MEK and PIK3CA downstream pathways are critical for colorectal tumor survival. The results lead to the question of whether these pathways should be considered as passengers instead of drivers.

Clinical Impact of Circulating Tumor RAS and BRAF Mutation Dynamics in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy Plus Anti-Epidermal Growth Factor Receptor Therapy.

PURPOSE: RAS and BRAF mutations can be detected as a mechanism of acquired resistance in circulating tumor (ct) DNA in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy. METHODS: RAS and BRAF mutational status was assessed in ctDNA in a baseline plasma sample and a serum sample collected at the time of the last available determination (named secondary extraction) from patients with KRAS exon 2 wild-type metastatic colorectal cancer treated in two first-line prospective biomarker-designed clinical trials (PULSE, ClinicalTrials.gov identifier: NCT01288339; and POSIBA, ClincialTrials.gov identifier: NCT01276379). RESULTS: Analysis of extended RAS and BRAF in tissue and plasma from 178 patients with KRAS exon 2 wild-type metastatic colorectal cancer showed a sensitivity of 64.1% and a specificity of 90%. The median overall survival (OS) of baseline patients with RAS and BRAF mutations in ctDNA was 22.3 months (95% CI, 15.6 to 29 months) and 8.9 months (95% CI, 6.3 to 11.4 months), respectively, which was significantly inferior to the median OS of 40.4 months (95% CI, 35.9 to 44.9 months) in two patients with wild-type disease (P < .001). Acquisition of RAS/BRAF mutations occurred in nine of 63 patients (14%) with progressive disease (PD; ie, blood draw within 1 month before PD or after PD) compared with six of 73 patients (8%) with no PD or blood extraction for ctDNA analysis before 1 month of PD (P = .47). Median OS in patients with RAS/BRAF acquisition was 23.9 months (95% CI, 19.7 to 27.9 months) compared with 40.6 months (95% CI, not reached to not reached) in patients who remained free of mutations (P = .016). CONCLUSION: Our results confirm that baseline RAS and BRAF testing in ctDNA discriminates survival. The emergence of RAS/BRAF mutations has limited relevance for the time to progression to anti-epidermal growth factor receptor therapy.

Adjuvant treatment in resected non-small cell lung cancer: current and future issues.

The cornerstone of treatment for early-stage non-small cell lung cancer (NSCLC) has been surgical resection. In the last five years two phase III trials have provided evidence of adjuvant platinum-based chemotherapy for completely resected stage II-IIIA patients. We review the evidence supporting adjuvant therapy in early-stage NSCLC; we discuss new issues surrounding adjuvant therapy such as treatment in the elderly-unfit population, treatment toxicity and its influence on outcomes, the importance of histology and gender in adjuvant treatment; and we discuss the future landscape of early-stage NSCLC research, namely, therapeutic strategies exploiting pharmacogenomic and gene-expression profiling, in an attempt to customize the treatment.

Malignant mesothelioma: new insights into a rare disease.

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy of the pleura associated with exposure to asbestos. Its incidence is anticipated to increase over the next 10years in both Europe and the developing nations. In advanced disease, chemotherapy is the cornerstone of treatment, especially platinum-containing regimens. Most efforts are directed toward improving standard first-line therapy or developing effective second-line therapy, which is still not yet standardized 10years after the first-line standard of care was established. This review focuses on the systemic management of MPM in patients who are not considered suitable for surgical approaches, and it discusses some questions that remain open such as the benefits of administering a maintenance treatment, whether it is better to give cisplatin or carboplatin as first-line therapy, the role of new drugs as second-line therapy, and the treatment of the elderly population. It also summarizes the results from clinical trials that have evaluated new treatments as first- or second-line therapy, which are based on the understanding of mesothelioma biology, such as antiangiogenic drugs, immunotherapies and growth factors agents.

Dos casos de metástasis hipofisarias como forma de presentación de un carcinoma microcítico de pulmón / Two cases of pituitary metastases as initial presentation form of small cell lung cancer

Las metástasis en la silla turca son raras y se encuentran en muchas ocasiones incidentalmente o en necropsias. Solo un 7% de los casos son sintomáticos. Las manifestaciones clínicas más frecuentes son la diabetes insípida, la clínica compresiva y los síntomas derivados de déficit hormonales de la adenohipófisis. Se presentan los casos de 2 varones con un carcinoma microcítico de pulmón cuya manifestación clínica inicial correspondía a afectación metastásica de la silla turca. Un caso debutó con invasión del seno cavernoso y panhipopituitarismo, y el otro con una diabetes insípida. Ambos casos presentaron una rápida progresión de su enfermedad neoplásica, con escasa respuesta al tratamiento sistémico en uno de los casos y fueron éxitus a los pocos meses. Las metástasis hipofisarias se presentan con mayor frecuencia en mujeres con cáncer de mama y hombres con neoplasias de pulmón. La presencia de poliuria y polidipsia en un paciente oncológico debe hacer sospechar una diabetes insípida, siendo necesario un estudio de imagen de la silla turca. El tratamiento de estos tumores incluye la cirugía, la radioterapia, la quimioterapia y el tratamiento hormonal sustitutivo. A pesar que el tratamiento quirúrgico no se ha asociado a un aumento de la supervivencia, algunos pacientes pueden mejorar su calidad de vida.

Metastases in the sellar region are rare and are frequently found incidentally or in necropsies. Only 7% are reported to be symptomatic. Diabetes insipidus, anterior pituitary dysfunction, visual field defects, headache/pain and ophthalmoplegia are the most commonly reported symptoms. We present the cases of two male patients with a small-cell lung carcinoma whose first clinical symptoms were due to pituitary metastasis. One case presented with symptoms of cavernous sinus invasion and panhypopituitarism and the other case with diabetes insipidus. Both patients had a rapid progression of their disease despite chemotherapy and died after a few months. Pituitary metastases occur most commonly with breast cancer in women and lung cancer in men. The presence of polyuria and polydipsia in an oncologic patient should alert the physician for diabetes insipidus and, if confirmed, an imaging procedure of the pituitary gland is mandatory. Treatment for these tumors is often multimodal and includes surgery, radiation therapy, chemotherapy and hormone replacement. Although surgical series have not shown any significant survival benefits given by tumor resection, the patient’s quality of life may be improved.

[Two cases of pituitary metastases as initial presentation form of small cell lung cancer]. / Dos casos de metástasis hipofisarias como forma de presentación de un carcinoma microcítico de pulmón.

Metastases in the sellar region are rare and are frequently found incidentally or in necropsies. Only 7% are reported to be symptomatic. Diabetes insipidus, anterior pituitary dysfunction, visual field defects, headache/pain and ophthalmoplegia are the most commonly reported symptoms. We present the cases of two male patients with a small-cell lung carcinoma whose first clinical symptoms were due to pituitary metastasis. One case presented with symptoms of cavernous sinus invasion and panhypopituitarism and the other case with diabetes insipidus. Both patients had a rapid progression of their disease despite chemotherapy and died after a few months. Pituitary metastases occur most commonly with breast cancer in women and lung cancer in men. The presence of polyuria and polydipsia in an oncologic patient should alert the physician for diabetes insipidus and, if confirmed, an imaging procedure of the pituitary gland is mandatory. Treatment for these tumors is often multimodal and includes surgery, radiation therapy, chemotherapy and hormone replacement. Although surgical series have not shown any significant survival benefits given by tumor resection, the patient's quality of life may be improved.

Increased ALK gene copy number and amplification are frequent in non-small cell lung cancer.

INTRODUCTION: Translocation of the anaplastic lymphoma kinase (ALK) gene is involved in the tumorigenesis of a subset of non-small cell lung carcinomas (NSCLCs) and identifies patients sensitive to ALK inhibitors. ALK copy number changes and amplification, which plays an oncogenic role in tumors such as neuroblastoma, are poorly characterized in NSCLC. We aimed to study the prevalence of ALK copy number changes and their correlation to ALK protein expression, epidermal growth factor receptor (EGFR) status, and clinicopathological data in patients with NSCLC. METHODS: ALK status was evaluated by fluorescence in situ hybridization (FISH). Specimens with ALK translocation were studied for echinoderm microtubule-associated protein-like 4 (EML4), KIF5B, and TFG status. ALK expression was assessed by immunohistochemistry. EGFR gene and protein status were evaluated in adenocarcinomas. Survival analysis was performed. RESULTS: One hundred seven NSCLC cases were evaluated. There were two cases of EML4-ALK translocation and one with an atypical translocation of ALK. Both cases of EML4-ALK translocation had ALK protein expression, whereas in the rest, ALK was undetected. Eleven cases (10%) exhibited ALK amplification and 68 (63%) copy number gains. There was an association between ALK amplification and EGFR FISH positivity (p < 0.0001) but not with prognosis. In conclusion, EML4-ALK translocation is a rare event in NSCLC. CONCLUSION: The study reveals a significant frequency of ALK amplification and its association with EGFR FISH positivity in lung adenocarcinomas. Based on these findings, a potential role of ALK amplification in the response to ALK inhibitors alone or combined with EGFR inhibitors in NSCLC merits further studies.