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Andrew Dean, Aisling Byrne, Mira Marinova, and Ingrid Hayden. Correspondence should be addressed to Andrew Dean;

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BioMed Research International Volume 2016, Article ID , 9 pages Research Article Clinical Outcomes of Patients with Rare and Heavily Pretreated Solid Tumors
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BioMed Research International Volume 2016, Article ID , 9 pages Research Article Clinical Outcomes of Patients with Rare and Heavily Pretreated Solid Tumors Treated according to the Results of Tumor Molecular Profiling Andrew Dean, Aisling Byrne, Mira Marinova, and Ingrid Hayden St John of God Hospital, Subiaco, WA 6008, Australia Correspondence should be addressed to Andrew Dean; Received 28 September 2015; Revised 25 February 2016; Accepted 10 April 2016 Academic Editor: Xia Li Copyright 2016 Andrew Dean et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Patients with heavily pretreated advanced cancer or with rare tumors are difficult to treat. Molecular profiling (MP) of tumors to identify biomarkers that predict potential outcomes with individual therapies is an emerging strategy to guide treatment decisions. Patients with rare tumors for which standard-of-care therapy was unavailable or more common tumors for which standardof-care options had been exhausted underwent MP at a single Australian center. Data regarding treating physicians choice of therapy, MP results and recommendations, and patient outcomes were collected. Seven patients had received prior standard firstline therapy (PST), 16 had rare tumors, and 31 had been heavily pretreated (HPT; 2 prior lines). Most treatments suggested by MP (541/594; 91.1%) were common chemotherapy drugs available in generic formulations. MP-guided therapy recommendations differed from physician s recommendations in 48 patients (88.9%). MP-guided therapy produced clinical benefit (improved QOL and/or performance status, symptoms, bodyweight, or RECIST) in 19/31 (61.3%), 11/16 (68.8%), and 3/7 (42.9%) patients with HPTs, rare tumors, and PSTs, respectively, and had a PFS ratio 1.3 in 22/37 evaluable patients (59.5%; 95% confidence interval 44 76%). The null hypothesis that 15% of these patients would have a PFS ratio 1.3 was rejected (one-sided p ). In conclusion, using MP to guide therapy selection is feasible in clinical practice and may improve patient outcomes. 1. Introduction Good performance status patients with heavily pretreated tumors and those with rare malignancies represent a difficult therapeutic group. The aim of therapy for these patients is to extend survival while maintaining the best possible quality of life (QOL); however, balancing the risks and benefits of treatment that is often not evidence based represents a significant challenge [1, 2]. Traditionally, cancer treatment selection has been based on tumor organ of origin and histological type rather than tumor molecular characteristics, despite increasing genetic heterogeneity as tumors metastasize, suggesting a hypothesis forwhyonlyaproportionofpatientsrespond[3].asour understanding of tumor biology has improved, increasing numbers of factors predicting sensitivity to therapy have been identified and can be used to guide therapy, with potential utility for both new targeted/biological agents and chemotherapy [4]. For example, the epidermal growth factor receptor- (EGFR-) targeted agent cetuximab was initially developed for colorectal cancers overexpressing EGFR, but subsequent analyses have demonstrated that KRAS wildtype and NRAS wild-type status identify those tumors that are most sensitive to cetuximab [5], resulting in a new standard molecular profiling test to guide treatment selection. Similarly, molecular testing can result in new treatment options becoming available; for example, EGFR2- (HER2-) directed therapies are now recommended by the National Comprehensive Cancer Network for the treatment of those relatively rare lung cancers that harbor HER2 mutations [6, 7]. Molecular profiling (MP) using comprehensive screening for multiple tumor biomarkers has the potential to identify therapies to which a tumor is most likely to be sensitive or resistant. By combining this information with the treating physician s knowledge of anticancer drug regimens and 2 BioMed Research International patient history, potentially effective regimens can be identified. Use of this technique in a variety of tumor types has been reported [8 13]. We describe a review of prospectively collected data for patients with difficult-to-treat tumors from a single center who underwent MP with a view to using the results to guide treatment decisions. 2. Materials and Methods 2.1. Patients. A single practice at St John of God Hospital, Subiaco,WesternAustralia,offeredMPtoaconsecutiveseries of good performance status patients with rare tumors with limited or no standard treatment options available and to those with common tumors who had exhausted standard treatment options. Patients who had received prior standard first-line therapy (PST) could request MP. All patients who underwent MP were included in the study, but those who died prior to receiving treatment or who subsequently opted out of MP-guided treatment were excluded from the efficacy analysis Molecular Profiling. MP was performed using the Caris Molecular Intelligence (CMI) platform. Using this platform, formalin-fixed paraffin-embedded tumor specimens were analyzed for multiple biomarkers using techniques such as immunohistochemistry, fluorescence/chromogenic in situ hybridization, quantitative polymerase chain reaction, and direct gene sequencing. Sample analysis is typically completed within 14 days. All biomarkers tested for are included in the panel based on the strength of supporting evidence as defined by the United States Preventative Services Task Force (USPSTF) level of evidence methodology [14]. The biomarker results are then interpreted to determine which of a panel of therapies is likely to provide benefit based on published evidence ( 95% of the associations included are supported by level 1 or level 2 evidence). The biomarker panel is updated based on ongoing literature review, meaning that the precise number of biomarkers analyzed for an individual patient varied Therapy Selection. Each patient had a best unprofiled treatment choice documented. However, the patient was treated based on the results of subsequent MP, with final treatment decisions being made based on a number of considerations. First, patients who had previously progressed on a drug that was identified as likely to provide benefit by MP were not retreated with the same drug because prior progression implies that other intracellular resistance pathways have become dominant. Second, where a number of different drugs were identified by MP as potentially beneficial, standard combination regimens were identified by the investigators and used (e.g., cisplatin plus gemcitabine; irinotecan plus 5-FU). Third, if there were reasons to exclude a particular drug or drug class (e.g., known severe hypersensitivity or prior intolerability), a regimen with less risk was chosen. Finally, where several drugs showed potential benefit and the factors above were unable to select between them, those drugs considered likely to provide most benefit by the investigators were selected Assessments. Treatment benefit was assessed after each treatment cycle based on factors including symptom relief and changes in bodyweight, pain, performance status, tumor marker levels, and patient-reported QOL. Tumors were imaged every 2 4 cycles. Response to treatment based on imaging was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) [15]. Progression-free survival (PFS) was defined as the time from the MP request until Eastern Cooperative Oncology Group (ECOG) performance status deterioration (assessed at each cycle of therapy) or progression as defined using RECIST [16]. To assess the benefit of MP-guided therapy, we used a previously described technique in which patients act as their own controls [13] by assessing the ratio between PFS on MPguided therapy and that on the most recent prior therapy. Von Hoff et al. defined a ratio of 1.3 as being indicative of clinical benefit with MP-guided therapy [13] Statistical Analysis. A one-sample one-sided proportion test was performed to test the null hypothesis that 15% of the patients would have a PFS ratio 1.3. This approach was basedonthatusedinthepreviousstudyreportedbyvonhoff et al. [13], which assumed a null response rate of 15% and analternativeresponserateof30%.theseassumptionswere used here. Considering these, the known sample size (n =37 with known PFS ratio), and an α risk of 5%, the power of the statistical test was 75%. 3. Results 3.1. MP Findings. Patient disposition is shown in Figure 1. Between March 5, 2012, and March 11, 2013, 98 consecutive patients who met the inclusion criteria were offered MP, with 54 patients undergoing MP and being treated according to the profile (Tables 1 3): 31 had heavily pretreated tumors (HPT; 2 prior lines); 16 had rare tumors; and 7 had received PST. PatientsintheHPTandraretumorgroupshadreceiveda median of 2 (ranges 2 4) and 1 (ranges 0 2) prior lines of therapy, respectively. MP identified a median of 18 (range 8 26) biomarkers associated with drugs with likely benefit (median 8; range 2 15) or lack of benefit (median 8; range 2 19) per patient in the HPT group, 16 (range 10 23; with benefit 7.5 [3 13],withoutbenefit 9[2 16]) per patient in the rare tumor group, and 13 (range 9 22; with benefit 5 [3 7], without benefit 10 [3 15]) per patient in the PST group. The proportion of biomarkers with benefit appeared to be greater in the HPT (47.6%) and rare tumor groups (45.3%) than in the PST group (36.9%). The majority of agents suggested by MP (541/594; 91.1%) were widely available chemotherapy drugs. Targeted/biological therapy recommendations were made predominantly for patients in the HPT group (45 of 53 targeted/biological agents recommended); reflecting this, the majority of the 16 patients in whom novel targeted/biological therapy recommendations weremadebasedonmpwereinthehptgroup(13patients). BioMed Research International 3 Tumor location Table 1: Tumor type and clinician and MP-guided therapy recommendation, MP results,and clinical outcomes: heavily pretreated group (HPT). Prior lines Next best treatment: clinician-defined Next best treatment: MP-defined Clinical Biomarkers observations a with/without benefit Chemotherapy versus biological/targeted therapy Cervical 2 Irinotecan + 5-FU (FOLFIRI started) CB 5/5 7 versus Gall bladder 3 FOLFIRI CB 3/5 5 versus Skin (Merckel) 3 Epirubicin + cisplatin + 5-FU P 4/5 8versus Colorectal 3 Mitoxantrone/5-FU Epirubicin + cisplatin + 5-FU P 4/5 8 versus Cervical 2 Nil FOLFIRI CB 15/4 10 versus Pancreas (adenocarcinoma) 2 Nil Epirubicin + cisplatin + 5-FU then trastuzumab (?)/erlotinib PFS ratio b CB 7/2 7 versus Gastric 2 FOLFIRI Gemcitabine + oxaliplatin CB 15/5 12versus Leiomyosarcoma 2 Trabectedin Sunitinib CB 11/6 9 versus Breast (ER /HER2 + ) 3 Trastuzumab/capecitabine then liposomal doxorubicin then trastuzumab/irinotecan Trastuzumab + irinotecan CB 15/9 20 versus Uterus 2 Doxorubicin + cyclophosphamide P 6/16 8versus Breast 2 Nab-paclitaxel (intolerant), cyclophosphamide + methotrexate + 5-FU P 8/11 17versus0 NA Small bowel 2 Died before assessment P 6/16 7versus0 NA Esophageal 2 FOLFIRI P 7/16 7 versus 2 NA Lung 2 Cisplatin + pemetrexed CB 14/12 7 versus Malignant mesothelioma 2 Cisplatin+pemetrexed Cisplatin+nab-paclitaxel +doxorubicin P 5/19 4versus0 NA Ovarian 3 Nab-paclitaxel Topotecan (also anthracyclines/nab-paclitaxel/hormones) CB 8/15 12 versus Cholangiocarcinoma 2 Epirubicin + cisplatin + 5-FU Cisplatin + gemcitabine CB 5/13 7versus 0 NA Mesothelioma 2 Nil FOLFIRI P 2/16 5 versus Gastrointestinal 2 FOLFIRI FOLFIRI P 4/18 5 versus Colon (adenocarcinoma) 2 Mitomycin-C + 5-FU Carboplatin + gemcitabine CB 13/8 10 versus Cervical 2 Irinotecan + 5-FU (FOLFIRI started) CB 5/5 7 versus Ovarian (serous adenocarcinoma) 2 Cisplatin + liposomal doxorubicin Carboplatin + liposomal doxorubicin CB 9/9 14 versus Lung (adenocarcinoma) 3 Vinorelbine Nab-paclitaxel P 10/11 9versus0 NA Pleura (adenocarcinoma) 3 FOLFIRI CB 9/6 11 versus Prostate 3 Mitoxantrone Irinotecan + 5-FU CB 12/5 16 versus Ovarian (serous adenocarcinoma) 2 Cisplatin + liposomal doxorubicin Cisplatin + liposomal doxorubicin CB 9/4 10 versus Ovarian (serous adenocarcinoma) 2 Cisplatin + liposomal doxorubicin Doxorubicin P 6/8 7 versus Colon (adenocarcinoma) 2 Gemcitabine + nab-paclitaxel P 8/9 8 versus Mesothelioma 2 Vinorelbine Gemcitabine + nab-paclitaxel CB 8/7 7 versus Gastric (adenocarcinoma) 2 Etoposide + leucovorin + 5-FU FOLFIRI CB 10/6 11 versus Ductal breast carcinoma 1 Nab-paclitaxel CB 10/3 16 versus 3 NA Totals CB = 19; P =12 253/ versus45 a CB = clinical benefit (QOL/PS/general symptoms/weight and imaging results improved or stable); NA = not available; P = progression (QOL/PS/general symptoms/weightandimagingresultsdeclinedor deteriorated). b Ratio of PFS with therapy suggested by MP versus that with prior line of therapy. FOLFIRI, irinotecan + 5-FU + folinic acid; PFS, progression-free survival; PS, performance status; QOL, quality of life. 4 BioMed Research International Table 2: Tumor type and clinician and MP-guided therapy recommendation, MP results,and clinical outcomes: rare tumorgroup. Tumor location Prior lines Next best treatment: clinician-defined Next best treatment: MP-defined Clinical Biomarkers observations a with/without benefit Chemotherapy versus biological/targeted therapy Ethmoid sinus 1 Pemetrexed CB 7/7 3 versus Adrenal cortex (adenocarcinoma) 2 FOLFIRI CB 6/15 16 versus Thyroid (anaplastic) 1 Nil FOLFIRI CB 7/3 12 versus Fibrosarcoma 0 Anthracyclines + dacarbazine (MAID) CB 7/16 16 versus 0 NA Astroblastoma 2 Temozolomide Temozolomide CB 4/9 5 versus 0 NA Pseudopapillary mucinous neoplasm 1 FOLFIRI Cisplatin + 5-FU CB 9/9 22 versus Endometrial stromal sarcoma 1 Tamoxifen (also platinum therapy, 5-FU, irinotecan, gemcitabine, and nab-paclitaxel) PFS ratio b P 9/9 22versus0 NA Medullary thyroid 0 Nil Carboplatin + nab-paclitaxel NED 3/19 7 versus 0 NA Adrenal cortical carcinoma 1 Nil Cyclophosphamide + doxorubicin + cisplatin P 11/1 17 versus 0 NA Liver leiomyosarcoma 2 Pazopanib Uterine carcinosarcoma 2 Fibrolamellar hepatocellular carcinoma Carcinoma with unknown primary (mediastinum) Cisplatin + liposomal doxorubicin Gemcitabine + nab-paclitaxel then nab-paclitaxel only CB 12/4 18 versus Cisplatin + liposomal doxorubicin P 5/11 6 versus Sorafenib FOLFIRI CB 8/7 9 versus Cisplatin + nab-paclitaxel CB 8/13 6 versus Adenoid cystic carcinoma of the maxilla (metastatic) 1 FOLFIRI CB 8/8 9 versus 0 NA Carcinoma with unknown primary (sacrum) 2 Cisplatin + gemcitabine CB 3/12 7 versus 0 NA Uterine leiomyosarcoma 3 Pazopanib Gemcitabine + nab-paclitaxel CB 13/2 21 versus 0 NA Totals 120/ versus 6 CB = 11; P =3; other = 2 a CB = clinical benefit (QOL/PS/general symptoms/weight and imaging results improved or stable); NA = not available; NED = no evaluable disease; P = progression (QOL/PS/general symptoms/weight and imaging results declined or deteriorated). b Ratio of PFS with therapy suggested by MP versus that with prior line of therapy. FOLFIRI, irinotecan + 5-FU + folinic acid; MAID, mesna + doxorubicin + ifosfamide + dacarbazine; PFS, progression-free survival; PS, performance status; QOL, quality of life. BioMed Research International 5 Table 3: Tumor type and clinician and MP-guided therapy recommendation, MP results,and clinical outcomes:prior standard first-line therapy group (PST). Tumor location Prior lines Next best treatment: clinician-defined Next best treatment: MP-defined Clinical Biomarkers observations a with/without benefit Chemotherapy versus biological/targeted therapy Lung 1 Docetaxel Carboplatin + nab-paclitaxel CB 5/6 4 versus Pancreas (adenocarcinoma) 1 FOLFIRINOX FOLFIRINOX P 5/7 8 versus 0 NA Melanoma 1 Fotemustine P 7/14 7 versus Lung (smallcell carcinoma) 1 FOLFIRI CB 5/10 8 versus Gall bladder 1 Epirubicin + cisplatin + 5-FU FOLFOX P 3/10 7 versus Lung (small cell carcinoma) 1 Docetaxel Cetuximab + FOLFIRI P 6/3 9 versus 1 NA Gastrointestinal (adenocarcinoma) 1 Carboplatin + nab-paclitaxel FOLFIRI CB 7/15 11 versus Totals CB = 3; P =4 38/65 54versus2 a CB = clinical benefit (QOL/PS/general symptoms/weight and imaging results improved or stable); NA = not available; P = progression (QOL/PS/general symptoms/weightandimagingresultsdeclinedor deteriorated). b Ratio of PFS with therapy suggested by MP versus that with prior line of therapy. FOLFIRI, irinotecan + 5-FU + folinic acid; FOLFOX, 5-FU + folinic acid + oxaliplatin; FOLFIRINOX, irinotecan + 5-FU + folinic acid + oxaliplatin; PFS, progression-free survival; PS, performance status; QOL, quality of life. PFS ratio b 6 BioMed Research International Patients attending practice (n = 964) Excluded (n = 910) (i) Not meeting inclusion criteria (n = 866) (ii) Declined to participate (n = 44) Included in analysis (n = 54) Heavily pretreated tumors (n = 31) Rare tumors (n = 16) Prior standard therapy (n = 7) (i) Clinical benefit (n = 19) (ii) Progression (n = 12) (i) Clinical benefit (n = 12) (ii) Progression (n = 3) (iii) No evaluable disease (n = 1) (i) Clinical benefit (n = 3) (ii) Progression (n = 4) Figure 1: Flow of patients in the study. The next best MP-guided therapy recommendation was the same as the physician s recommendation in only six patients overall (11.1%) Treatment Outcomes. Clinical benefit (improved QOL and/or performance status, symptoms, bodyweight, or RECIST) was observed in 19/31 (61.3%), 11/16 (68.8%), and 3/7 (42.9%) patients in the HPT, rare tumor, and PST groups, respectively (Tables 1 3). Data on the PFS ratio were available for 37 of 54 patients (HPT, 24/31; rare tumors, 8/16; PST, 5/7) (Tables 1 3; Figure2).Ofthese37patients,22(59.5%)hadaPFSratio 1.3 (HPT, 14/24 [58.3%]; rare tumors, 6/8 [75.0%]; PST, 2/5 [40.0%]) (95% confidence interval: 44 76%). The null hypothesis that 15% of these patients would have a PFS ratio 1.3 was rejected (one-sided p ). The median PFS ratio was 1.75 for those categorized as having a response and 0.80 for those who did not have a response. Although targeted/biological therapies were recommended by MP in 16 patients, only four patients were treated with targeted/biological therapy. Three of the 13 patients in the HPT group in whom targeted/biological therapy was identified as being of potential benefit by MP received it: one patient with heavily pretreated leiomyosarcoma that responded to MP-guided sunitinib (PFS ratio 14.87); one patient with metastatic breast cancer that responded to trastuzumab combined with irinotecan (PFS ratio 0.67); and one patient with pancreatic adenocarcinoma that responded rapidly to trastuzumab + erlotinib after failing MP-guided epirubicin + cisplatin + 5-FU (ECF) (PFS ratio 1.33). One patient with a PST tumor (small-cell lung cancer) received targeted/biological therapy (cetuximab + FOLFIRI), without apparentbenefit;another,alsowithsmall-celllungcancer, in whom targeted/biological therapy was suggested but not used,showedarecistresponseandstableqolandperformance status with MP-guided FOLFIRI (PFS ratio 0.80). In most of the other cases, the recommended targeted/biological therapy was either not funded or not available and MP-guided chemotherapy was used instead. Individual patients showing noteworthy responses includedthreeinthehptgroup,twowithsignificantshrinkage on imaging of cervical tumors treated with MP-guided irinotecan + 5-FU (PFS ratios 1.91 and 2.00), and a promising response to gemcitabine + nab-paclitaxel (stable disease with improved QOL, performance status, and symptoms) in a patient with mesothelioma (PFS ratio 0.30; survival 7.0 months). All three patients showed improved performance status and experienced clinically significant pain relief. In the rare tumor group, a patient with anaplastic thyroid disease who had previously h
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