Outcome according to residual disease (surgeon's report vs pre-chemotherapy imaging) in patients with bevacizumab-treated ovarian cancer: Analysis of the ROSiA study.

BACKGROUND AND OBJECTIVES: The single-arm ROSiA study evaluated frontline bevacizumab for advanced ovarian cancer. We explored how discordant surgically and radiologically assessed postoperative residual disease affects outcomes. METHODS: After debulking surgery, 1021 patients received 4 to 8 cycles of carboplatin-paclitaxel plus bevacizumab until progression or up to 24 months. The primary endpoint was safety; progression-free survival (PFS) was a secondary endpoint. We performed post hoc exploratory PFS analyses in four subgroups: surgeon-reported no visible residuum (NVR) without target lesions; surgeon-reported NVR with target lesions; macroscopic (≤1 cm) residuum; and >1 cm residuum. RESULTS: Surgical and radiological assessments were concordant in 94% of patients; 61 patients (6%; 21% of those with surgeon-reported NVR) had NVR with target lesions. Median PFS was numerically longest in patients with concordant surgically/radiologically assessed NVR (35.5 months), intermediate for surgeon-reported NVR with target lesions (31.8 months), and shortest for visible residuum (27.9 and 20.2 months for visible residuum ≤1 and >1 cm, respectively). One-year and 2-year PFS rates showed the same pattern. CONCLUSIONS: These analyses suggest that prognosis is potentially worse in patients with radiologically detected target lesions despite surgeon-reported NVR compared with concordant NVR by both assessment methods. Postsurgical imaging may add valuable prognostic information.

Efficacy and safety results from GEICO 1205, a randomized phase II trial of neoadjuvant chemotherapy with or without bevacizumab for advanced epithelial ovarian cancer.

BACKGROUND: Bevacizumab is an approved treatment after primary debulking surgery for ovarian cancer. However, there is limited information on bevacizumab added to neoadjuvant chemotherapy before interval debulking surgery. OBJECTIVE: To evaluate neoadjuvant bevacizumab in a randomized phase II trial. METHODS: Patients with newly diagnosed stage III/IV high-grade serous/endometrioid ovarian cancer were randomized to receive four cycles of neoadjuvant chemotherapy with or without ≥3 cycles of bevacizumab 15 mg/kg every 3 weeks. After interval debulking surgery, all patients received post-operative chemotherapy (three cycles) and bevacizumab for 15 months. The primary end point was complete macroscopic response rate at interval debulking surgery. RESULTS: Of 68 patients randomized, 64 completed four neoadjuvant cycles; 22 of 33 (67%) in the chemotherapy-alone arm and 31 of 35 (89%) in the bevacizumab arm (p=0.029) underwent surgery. The complete macroscopic response rate did not differ between treatment arms in either the intention-to-treat population of 68 patients (6.1% vs 5.7%, respectively; p=0.25) or the 55 patients who underwent surgery (8.3% vs 6.5%; p=1.00). There was no difference in complete cytoreduction rate or progression-free survival between the treatment arms. During neoadjuvant therapy, grade ≥3 adverse events were more common with chemotherapy alone than with bevacizumab (61% vs 29%, respectively; p=0.008). Intestinal (sub)occlusion, fatigue/asthenia, abdominal infection, and thrombocytopenia were less frequent with bevacizumab. The incidence of grade ≥3 adverse events was 9% in the control arm versus 16% in the experimental arm in the month after surgery. CONCLUSIONS: Adding three to four pre-operative cycles of bevacizumab to neoadjuvant chemotherapy for unresectable disease did not improve the complete macroscopic response rate or surgical outcome, but improved surgical operability without increasing toxicity. These results support the early integration of bevacizumab in carefully selected high-risk patients requiring neoadjuvant chemotherapy for initially unresectable ovarian cancer.

Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials.

BACKGROUND: Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations. METHODS: We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial (NCT00003636) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic. FINDINGS: Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0-9·6; EORTC, 9·2 years [IQR 7·3-10·4]; CHORUS, 5·9 years [IQR 4·3-7·4]). Median age was 63 years (IQR 56-71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8-13·0). 55 (5%) women had FIGO stage II-IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1-51·3] and 26·9 months [12·7-50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86-1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7-53·7) and 23·6 months (10·5-46·9), respectively (HR 1·20, 95% CI 1·06-1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1-47·6] and 21·2 months [10·0-36·4], respectively; HR 0·76, 95% CI 0·58-1·00; p=0·048; median progression-free survival 10·6 months [7·9-15·0] and 9·7 months [5·2-13·2], respectively; HR 0·77, 95% CI 0·59-1·00; p=0·049). INTERPRETATION: Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC-IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status. FUNDING: National Cancer Institute and Vlaamse Liga tegen kanker (Flemish League against Cancer).

Safety and Efficacy of Extended Bevacizumab Therapy in Elderly (≥70 Years) Versus Younger Patients Treated for Newly Diagnosed Ovarian Cancer in the International ROSiA Study.

OBJECTIVE: The single-arm ROSiA study explored an extended duration of frontline bevacizumab-containing therapy for ovarian cancer. Post hoc analyses explored safety and efficacy according to age. PATIENTS AND METHODS: After primary debulking surgery, patients with stage IIB-IV or grade 3 stage I-IIA ovarian cancer received 4-8 cycles of paclitaxel [weekly or every 3 weeks (q3w)], carboplatin AUC 5-6 q3w, and bevacizumab 15 (or 7.5) mg/kg q3w, followed by single-agent bevacizumab until progression or for up to 24 months. The primary end point was safety; progression-free survival (PFS) was a secondary end point. RESULTS: Of 1021 patients treated, 121 (12%) were aged 70 years or older and 44 (4%) were 75 years or older. Compared with younger patients, more patients aged 70 years or older had hypertension at baseline, stage IV disease, and Eastern Cooperative Oncology Group performance status 1 or above. Bevacizumab was continued for more than 15 months in 49% of older versus 53% of younger patients. Older patients experienced higher incidences of all-grade anemia (44% vs 32%), diarrhea (35% vs 25%), and asthenia (22% vs 12%), and grade ≥3 hypertension (41% vs 22%) and thromboembolic events (7% vs 2%) compared with younger patients. Fatal bevacizumab-related adverse events occurred in 1 (0.8%) older versus 5 (0.6%) younger patients. Median PFS was 23.7 (95% confidence interval, 18.6-27.9) versus 25.6 (95% confidence interval, 23.7-28.4) months in patients aged 70 or older versus those younger than 70 years, respectively. CONCLUSION: Bevacizumab-treated patients aged 70 years or older had higher incidences of anemia, low-grade diarrhea, and asthenia, and grade ≥3 hypertension and thromboembolic events than those younger than 70 years, but no other relevant increase in toxicity. Median PFS of approximately 2 years is similar to that in younger patients despite the worse prognosis. Older age should not preclude bevacizumab therapy for ovarian cancer in carefully selected patients aged 70 years or older. Given the higher background hypertension prevalence, elderly patients should be monitored more closely while receiving bevacizumab.

Efficacy and Safety of Bevacizumab-Containing Therapy in Newly Diagnosed Ovarian Cancer: ROSiA Single-Arm Phase 3B Study.

OBJECTIVE: The aim of this study was to assess the safety and efficacy of extending bevacizumab therapy beyond 15 months in nonprogressive ovarian cancer. PATIENTS AND METHODS: In this multinational prospective single-arm study (ClinicalTrials.gov NCT01239732), eligible patients had International Federation of Gynecology and Obstetrics stage IIB to IV or grade 3 stage I to IIA ovarian cancer without clinical signs or symptoms of gastrointestinal obstruction or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the preceding 6 months. Prior neoadjuvant chemotherapy was permitted. After debulking surgery, patients received bevacizumab 15 (or 7.5) mg/kg every 3 weeks (q3w) with 4 to 8 cycles of paclitaxel (investigator's choice of 175 mg/m q3w or 80 mg/m weekly) plus carboplatin AUC 5 to 6 q3w. Single-agent bevacizumab was continued until progression or for up to 24 months. The primary end point was safety. RESULTS: Between December 2010 and May 2012, 1021 patients from 35 countries began study treatment. Bevacizumab was administered at 15 mg/kg in 89% of patients and for more than 15 months in 53%. Median follow-up duration was 32 months (range, 1-50 months). The most common all-grade adverse events were hypertension (55% of patients), neutropenia (49%), and alopecia (43%). The most common grade 3 or higher-grade adverse events were neutropenia (27%) and hypertension (25%). Bevacizumab was discontinued because of proteinuria in 5% of patients and hypertension in 3%. Median progression-free survival (PFS) was 25.5 months (95% confidence interval, 23.7-27.6 months). CONCLUSION: Extended bevacizumab demonstrated increased incidences of proteinuria and hypertension compared with 12 or 15 months of bevacizumab in previous trials, but these rarely led to bevacizumab discontinuation. Median PFS is the longest reported for frontline bevacizumab-containing therapy. The longer bevacizumab duration beyond 15 months in this study may improve PFS without substantially compromising safety.

Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer.

BACKGROUND: Primary debulking surgery before initiation of chemotherapy has been the standard of care for patients with advanced ovarian cancer. METHODS: We randomly assigned patients with stage IIIC or IV epithelial ovarian carcinoma, fallopian-tube carcinoma, or primary peritoneal carcinoma to primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant platinum-based chemotherapy followed by debulking surgery (so-called interval debulking surgery). RESULTS: Of the 670 patients randomly assigned to a study treatment, 632 (94.3%) were eligible and started the treatment. The majority of these patients had extensive stage IIIC or IV disease at primary debulking surgery (metastatic lesions that were larger than 5 cm in diameter in 74.5% of patients and larger than 10 cm in 61.6%). The largest residual tumor was 1 cm or less in diameter in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. Postoperative rates of adverse effects and mortality tended to be higher after primary debulking than after interval debulking. The hazard ratio for death (intention-to-treat analysis) in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 0.84 to 1.13; P=0.01 for noninferiority), and the hazard ratio for progressive disease was 1.01 (90% CI, 0.89 to 1.15). Complete resection of all macroscopic disease (at primary or interval surgery) was the strongest independent variable in predicting overall survival. CONCLUSIONS: Neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary debulking surgery followed by chemotherapy as a treatment option for patients with bulky stage IIIC or IV ovarian carcinoma in this study. Complete resection of all macroscopic disease, whether performed as primary treatment or after neoadjuvant chemotherapy, remains the objective whenever cytoreductive surgery is performed. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003636.)

Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.

BACKGROUND: Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. METHODS: The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0-56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. FINDINGS: The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio [HR] 0·76; 95% CI 0·66-0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3%vs 87·7%, respectively; HR 0·85; 95% CI 0·70-1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5-52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51-0·90; p=0·0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. INTERPRETATION: Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. FUNDING: F Hoffmann-La Roche, Michelangelo Foundation.

Bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer.

AIM: To retrospectively assess the efficacy and safety of bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. PATIENTS AND METHODS: Patients with recurrent ovarian cancer and prior treatment with platinum- and taxane-based chemotherapy were included. Treatment consisted of bevacizumab 10 mg/kg intravenously every 2 weeks plus oral cyclophosphamide 50 mg daily until disease progression or unacceptable toxicity. Response rates (RR) were determined according to RECIST criteria and by monitoring the CA 125 serum tumor marker according to Rustin's criteria. The endpoints were progression-free survival (PFS), RR, overall survival (OS), and safety. RESULTS: Thirty-eight patients were treated; 79% were platinum resistant and 21% were platinum sensitive. The median number of previous treatments was 4 (range 1-8). Seventy-nine percent of patients had received more than 2 previous lines of treatment. Eighty-one percent of patients had received gemcitabine, 76% liposomal doxorubicin, and 50% topotecan. A median of 8 (range 1-70) cycles of bevacizumab were administered. The overall RR was a complete response (CR) in 3 patients (8.1%), a partial response (PR) in 12 (32.4%), and stable disease (SD) ≥6 months in 3 (8.1%). The median PFS and OS were 4.5 and 10.7 months, respectively. Thirty-nine percent of patients were progression free for at least 6 months. In an exploratory analysis there was a significant relation of prior platinum response and performance status with the risk of progression. Grade 3-4 toxicities included anemia (1), hypertension (2), hematuria (1), arterial thrombosis in the leg (1), dyspnea (1), and intestinal fistulae (1). There were no cases of gastrointestinal perforation (GIP) or treatment-related deaths. CONCLUSION: The combination of bevacizumab and metronomic cyclophosphamide was active and well-tolerated in heavily pretreated patients with recurrent ovarian cancer.

Cisplatin-based radiochemotherapy improves the negative prognosis of c-erbB-2 overexpressing advanced cervical cancer.

OBJECTIVES: To determine the impact of c-erb-B2 overexpression on disease-free survival (DFS) and local relapse in patients with advanced cervical cancer (CC) receiving concurrent chemoradiotherapy treatment. METHODS: A total of 136 patients with advanced CC (FIGO stage: IB2-IIA [12]; IIB [34]; IIIB [71]; IVA [19]; including both epidermoid [86] and adenocarcinoma [14]) were analyzed to determine c-erb-B2 levels by immunohistochemistry (c-erb-B2 antibody; Dako, Glostrup, Denmark). Only c-erb-B2+++ biopsies were considered positive. All patients received pelvic radiotherapy, brachytherapy, and concurrent chemotherapy with 2 different regimens: 48 patients were treated with tegafur (800 mg/d orally) and 88 with tegafur (same doses) plus 5 cycles of weekly cisplatin 40 mg/m/wk intravenously. RESULTS: A total of 32 (23.5%) biopsies were considered c-erb-B2-positive. Three-year and 5-year DFS were 61% and 58% for c-erb-B2-negative patients and 36% and 36% for c-erB2-positive patients, respectively (P = 0.02). Patients were stratified in 4 groups according to their c-erb-B2 status and whether they received cisplatin. The group of patients with c-erb-B2 overexpression that did not receive platinum treatment had a higher rate of pelvic relapse (P < 0.0001), associated with a decreased DFS (P = 0.0014). CONCLUSIONS: c-erb-B2 overexpression may imply a poor prognosis for patients with advanced CC. Treatment with cisplatin-based radiochemotherapy improved outcome in these patients.

Negative prognostic impact of the coexpression of epidermal growth factor receptor and c-erbB-2 in locally advanced cervical cancer.

OBJECTIVE: The objective was to determine the impact of the coexpression of epidermal growth factor receptor (EGFR) and tumor marker c-erbB-2 on disease-free survival (DFS) and pelvic relapse-free survival (PRFS) in patients with locally advanced cervical cancer (LACC) receiving concurrent chemoradiotherapy. METHODS: The expression of EGFR and c-erbB-2 was assessed by immunohistochemistry, which was centralized and blinded to outcome. Univariate and multivariate analyses were used to evaluate the impact of EGFR and c-erbB-2 on DFS and PRFS. RESULTS: 170 patients with LACC were included and received concurrent chemoradiotherapy. 25 (15%) biopsies were considered EGFR and c-erbB-2 positive; 100 (59%) were either EGFR or c-erbB-2 positive, and 45 (26%) were EGFR and c-erbB-2 negative. The 3- and 5-year DFS was 39% each for EGFR- and c-erbB-2-positive patients, 54 and 49%, respectively, for EGFR- or c-erbB-2-positive patients, and 76 and 72%, respectively, for EGFR- and c-erbB-2-negative patients (p = 0.006). EGFR- and c-erbB-2-positive tumors were significantly associated with a decrease in PRFS (hazard ratio, HR, 3.99; 95% confidence interval, CI, 1.44-11.05, p = 0.007), and DFS (HR 2.9; 95% CI, 1.26-6.66, p = 0.01). CONCLUSION: Patients with LACC coexpressing EGFR and c-erbB-2, and treated with concurrent chemoradiotherapy, had a worse clinical prognosis with shorter DFS and PRFS.

Proteomics characterisation of central nervous system metastasis biomarkers in triple negative breast cancer.

BACKGROUND: Breast cancer (BC) is the most frequent tumour in women. Triple negative tumours (TNBC)-which are associated with minor survival rates-lack markers predictive of response to anticancer drugs. Triple negative tumours frequently metastasise to the central nervous system (CNS). OBJECTIVE: The main objective of this study was to study differences in tumour protein expression between patients with CNS metastases and those without this kind of spread, and propose new biomarkers. METHODS: A retrospective study was performed. Targeted proteomics and statistical analyses were used to identify possible biomarkers. RESULTS: Proteins were quantified by a targeted proteomics approach and protein expression data were successfully obtained from 51 triple negative formalin-fixed paraffin-embedded samples. ISG15, THBS1 and AP1M1 were identified as possible biomarkers related with CNS metastasis development. CONCLUSIONS: Three possible biomarkers associated with CNS metastases in TNBC tumours were identified: ISG15, THBS1 and AP1M1. They may become markers predicting the appearance of CNS infiltration in triple negative BC.

Lapatinib plus trastuzumab in pretreated human epidermal growth factor receptor 2-positive metastatic breast cancer.

BACKGROUND: Dual human epidermal growth factor receptor 2 (HER2) blockade has been preclinically and clinically assessed in HER2-overexpressing metastatic breast cancer (mBC) with encouraging results. PATIENTS AND METHODS: This is a descriptive retrospective study of trastuzumab plus lapatinib activity in patients with HER2-overexpressing mBC from two centers. The primary endpoints were to assess objective response rate (ORR) and toxicity. The secondary endpoints were to assess progression-free survival (PFS) and overall survival. RESULTS: A total of 23 HER2-positive mBC patients previously treated with trastuzumab received a trastuzumab plus lapatinib based therapy. Chemotherapy (CT) was added to the dual HER2 blockade treatment in 13 patients (56%), whereas hormonotherapy (HT) was added in 8 patients (35%) and 2 patients (9%) received lapatinib plus trastuzumab without any other agent. ORR was 22% (5/23) and 39% (9/23) of patients had stable disease. PFS in the overall population was 4 months. PFS in patients with CT was 5 months, whereas PFS in patients with HT was 2 months. Grade≥3 adverse events were diarrhea (26%) and hand-and-foot syndrome (9%). CONCLUSIONS: These findings suggest that dual HER2 blockade in combination with CT is feasible in pretreated HER2-positive mBC patients.

The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy.

BACKGROUND: Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment. METHODS: Data were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples. RESULTS: 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. CONCLUSIONS: Trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.

Is capecitabine a new choice of treatment for lung adenocarcinoma? A case report involving partial response in second line of treatment and hypothesis of the biological basis.

In lung cancer different histologies have different biologies. Active agents in non-small-cell lung cancer (NSCLC) include platinums, paclitaxel, docetaxel, gemcitabine, erlotinib, pemetrexed and vinorelbine. We report a case of a patient with metastatic lung adenocarcinoma with high levels of LDH and CEA with clear partial response to capecitabine after several lines of chemotherapy. The increase in thymidine phosphorylase (TP) expression in NSCLC could provide a rationale for the use of capecitabine in this tumour. More research is needed to try to explain the striking activity of capecitabine in this patient with lung adenocarcinoma and high levels of CEA and to find molecular targets to predict the response to this agent.