Objective Responses In Patients Research Articles

Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas

The serine/threonine kinase B-Raf plays a key role in the Ras/Raf/MEK/ERK pathway that relays extracellular signals for cell proliferation and survival. Several types of human malignancies harbor activating BRAF mutations, most frequently a V600E substitution. The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase (TK) receptor that mediates proliferation and survival signaling, is expressed in a wide variety of normal and neoplastic tissues. EGFR inhibitors have produced objective responses in patients with non-small cell lung carcinomas harboring activating EGFR TK domain somatic mutations. We evaluated the presence of mutations in BRAF (exons 11 and 15), KRAS (exons 1 and 2), NRAS (exons 1 and 2), and EGFR (exons 18-21) in adrenal carcinomas (35 tumor specimens and two cell lines) by DNA sequencing. BRAF mutations were found in two carcinomas (5.7%). Four carcinomas (11.4%) carried EGFR TK domain mutations. One specimen carried a KRAS mutation, and another carried two NRAS mutations. No mutations were found in the two adrenocortical cell lines. BRAF- and EGFR-mutant tumor specimens exhibited stronger immunostaining for the phosphorylated forms of the MEK and ERK kinases than their wild-type counterparts. EGFR-mutant carcinomas exhibited increased phosphorylation of EGFR (Tyr 992) compared with wild-type carcinomas. We conclude that BRAF, RAS, and EGFR mutations occur in a subset of human adrenocortical carcinomas. Inhibitors of the Ras/Raf/MEK/ERK and EGFR pathways represent candidate targeted therapies for future clinical trials in carefully selected patients with adrenocortical carcinomas harboring respective activating mutations.

Interleukin 2 for patients with renal cancer

Interleukin 2 (IL-2) is the only systemic treatment currently available that is capable of curing patients with metastatic renal cell cancer (RCC). The first indications that IL-2 could mediate objective responses in patients with metastatic RCC were reported in 1985. On the basis of the durability of the complete responses in multiple trials, the FDA approved high-dose IL-2 for the treatment of patients with metastatic RCC in 1992. In the Surgery Branch of the National Cancer Institute, a 20% objective response rate (9% complete and 11% partial) was seen in 259 consecutive patients with metastatic RCC treated with high-dose IL-2 alone, with only 2 treatment-related deaths. Among the 23 patients showing a complete response, disease recurrence has occurred in only 4 patients; the remaining 19 patients all have ongoing responses of between 2 and 18 years. These results indicate that over 80% of all patients who obtain a complete response following high-dose IL-2 never experience disease recurrence and seem to be cured of their disease. In the August 2007 issue of this journal, two Practice Point articles reviewed the recently published studies that evaluate the multikinase inhibitors sorafenib and sunitinib for the treatment of patients with metastatic RCC. Treatment with these agents resulted in the prolongation of disease-free survival, and on this basis sorafenib and sunitinib were approved by the FDA. There were no complete responses in the 335 patients who received sunitinib and one complete response in the 451 patients who received sorafenib. In the commentary on the sorafenib paper, Twardowski and Figlin appropriately concluded that sorafenib is “primarily indicated as a second-line treatment for patients…who develop progressive disease after cytokine therapy”. In the commentary of the paper on sunitinib, however, Stadler and Szmulewitz concluded that sunitinib is a “reasonable first-line agent, especially in patients with good or intermediate prognosis, and is a standard of care”. They base this statement on the comment that IL-2 is “toxic and not feasible for most patients”. Stadler and Szmulewitz, therefore, advocate the use of sunitinib, despite the fact that this agent cures virtually no one, whereas high-dose IL-2 apparently cures about 8% of patients. High-dose IL-2 has been considerably underused in the treatment of patients with metastatic RCC, because it is inconvenient to administer and results in types of toxicity not common in the practice of medical oncologists. It must be administered as an inpatient procedure at 8-hour intervals and each dose needs to be administered to patient tolerance. The major toxicities of high-dose IL-2 result from a capillary-leak syndrome, which leads to fluid extravasation into tissue, hypotension and oliguria, all of which are reversible with no long-term sequelae. Physicians with experience in the use of high-dose IL-2 can very safely administer this agent to patients with normal cardiac and renal function. Careful monitoring and fluid replacement can solve virtually all of the problems associated with IL-2 administration. Many oncologists, comfortable with severe and prolonged neutropenia and thrombocytopenia, seem unwilling to contend with the physiologic disturbances caused by high-dose IL-2 administration. Decisions about the use of IL-2 seem to be more related to the training of oncologists than to the effectiveness of the treatment. IL-2 should be the first-line treatment for patients with metastatic RCC. Most patients would not refuse to undertake this treatment if they were informed that it was the only chance of eradicating their disease and that the benefits far outweighed the risks. Sorafenib and sunitinib are valuable adjuncts for the treatment of these patients, but should most appropriately be used as second-line agents.

Immuntherapie des metastasierten Nierenzellkarzinoms mit Interleukin-2, Interferon-α2a und Erythropoetin-β

The combination of interferon-alpha2a (IFN-alpha2a) and interleukin-2 (IL-2) induces objective responses in patients with metastatic renal cell carcinoma (MRCC). Anaemia is associated with poor cancer control and reduced quality of life. The aim of the study was to investigate response rate and quality of life in patients with MRCC receiving the combination of Erythropoetin, IFN-alpha2a and IL-2. Patients with MRCC received epoetin beta (150 IU/kg and haemoglobin <130 g/l or 75 IU/kg and haemoglobin >or=130 g/l) three times weekly, from 14 days before and continuing throughout immunotherapy. In weeks 3-6 the patients received IFN-alpha2a 6 x 10(6) IU/m2 and IL-2 4.5 x 10(6) IU/m2 three times weekly on days 1, 3 and 5. The treatment was repeated two times and in the case of success a third cycle was added. The quality of life was assessed with the FACT questionnaire for fatigue, before, during and after therapy. A total of 21 patients were treated, 19 of whom could be evaluated concerning response, toxicity and quality of life. We observed 1 complete remission, 2 partial remissions, 5 cases of stable disease and 11 with progressive disease. The overall response rate was 16%. Toxicity was mild to moderate; there were no WHO grade III or IV toxicity. The quality of life increased in ten patients, nine of whom exhibited an increase in their haemoglobin during therapy. Five of the nine patients with decreased quality of life also experienced a decrease in their haemoglobin. The correlation of increased haemoglobin and quality of life was significant (p<0.05). The combination of IFN-alpha2a, IL-2 and epoetin beta resulted in objective remissions with mild to moderate toxicity. The quality of life correlates significantly with increasing haemoglobin.

Exploiting the apoptotic actions of oestrogen to reverse antihormonal drug resistance in oestrogen receptor positive breast cancer patients

The ubiquitous application of selective oestrogen receptor modulators (SERMs) and aromatase inhibitors for the treatment and prevention of breast cancer has created a significant advance in patient care. However, the consequence of prolonged treatment with antihormonal therapy is the development of drug resistance. Nevertheless, the systematic description of models of drug resistance to SERMs and aromatase inhibitors has resulted in the discovery of a vulnerability in tumour homeostasis that can be exploited to improve patient care. Drug resistance to antihormones evolves, so that eventually the cells change to create novel signal transduction pathways for enhanced oestrogen (GPR30+OER) sensitivity, a reduction in progesterone receptor production and an increased metastatic potential. Most importantly, antihormone resistant breast cancer cells adapt with an ability to undergo apoptosis with low concentrations of oestrogen. The oestrogen destroys antihormone resistant cells and reactivates sensitivity to prolonged antihormonal therapy. We have initiated a major collaborative program of genomics and proteomics to use our laboratory models to map the mechanism of subcellular survival and apoptosis in breast cancer. The laboratory program is integrated with a clinical program that seeks to determine the minimum dose of oestrogen necessary to create objective responses in patients who have succeeded and failed two consecutive antihormonal therapies. Once our program is complete, the new knowledge will be available to translate to clinical care for the long-term maintenance of patients on antihormone therapy.

Epidermal Growth Factor Receptor as a Therapeutic Target in Human Thyroid Carcinoma: Mutational and Functional Analysis

The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase (TK) receptor that mediates proliferation and survival signaling, is expressed in a wide variety of normal and neoplastic tissues. EGFR inhibitors have produced objective responses in patients with non-small-cell lung carcinomas harboring activating EGFR TK domain somatic mutations. Because the EGFR pathway has been reported to be important for the pathophysiology of thyroid carcinoma, we investigated the expression and mutational status of EGFR in 14 thyroid carcinoma cell lines as well as its functional role by evaluating their in vitro sensitivity to AEE788, a new dual-family EGFR/ErbB2 and vascular endothelial growth factor receptor TK inhibitor. We also evaluated the mutational status, mRNA and protein expression, as well as phosphorylation status of EGFR in a panel of thyroid carcinoma specimens. EGFR expression and phosphorylation in the thyroid carcinoma cell lines and tissue specimens were present but not stronger than in noncancerous thyroid tissue. EGFR TK domain mutations were detected in two of 62 histological specimens (3.2%) but not in cell lines. All thyroid carcinoma cell lines were significantly less sensitive (IC(50) at least 25-fold higher) in vitro to AEE788 than a primary culture of EGFR-mutant lung carcinoma cells. Thyroid carcinoma cells overall are poorly responsive to clinically relevant concentrations of AEE788 in vitro. The presence of EGFR-activating TK domain mutations may identify a small minority of thyroid cancer patients that may benefit from EGFR inhibitors, but additional preclinical evidence of efficacy is needed.

Objective Responses in Patients with Malignant Melanoma or Renal Cell Cancer in Early Clinical Studies Do Not Predict Regulatory Approval

Tumor responses in early-phase trials are used to determine whether new agents warrant further study. Given that spontaneous regressions are observed in melanoma and renal cell carcinoma, this study assessed whether tumor responses, particularly in these two tumor types, predict for future regulatory drug approval. The literature was reviewed to assess tumor response rates to cytotoxic agents in phase I and II trials in the following solid tumors: melanoma, renal cell carcinoma, non-small-cell lung cancer, breast cancer, ovarian cancer, colorectal cancer, and other solid tumors. Response rates were categorized and the relationship of these categories to the end point of regulatory drug approval was determined. Fifty-eight drugs were assessed in 100 phase I trials, and 46 of these drugs were also studied in 499 phase II trials. Higher overall response rates in both phase I trials (P = 0.03) and phase II trials (P < 0.0001) were predictive of regulatory approval. However, response in melanoma or renal cell carcinoma was not predictive for either phase I or phase II studies. For cytotoxic agents, although overall objective response rates reliably predict subsequent marketing approval, isolated responses in melanoma and renal cell carcinoma are not predictive.

Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment

Treatment of acute graft-versus-host disease (aGVHD) has relied on high-dose steroids, but less than 50% of patients show durable remission. Antithymocyte globulin (ATG) has become a standard salvage therapy. We now report our experience with ATG for the treatment of steroid-refractory GVHD in 69 patients treated from January 1, 1980, to May 1, 1999. Patients with GVHD were given an overall grade using standard criteria. Overall responses were similar to those in previously published literature. However, long-term survival for this group of patients was dismal. Of the 69 patients treated with ATG for steroid-refractory GVHD, only 3 (5%) are currently alive. The median survival of these patients by GVHD grade was 4.1 months for grade 2, 3.6 months for grade 3, and 2.7 months for grade 4. The age range of the surviving patients was 3 to 25 years. Only 5% of the deaths were due to relapse, with the remaining deaths due to GVHD, infection, and/or organ failure. In conclusion, ATG treatment can produce objective responses in patients with aGVHD, but these responses do not result in long-term survival. Given the poor survival rates of patients treated with ATG for steroid-refractory GVHD, treatment with ATG as standard therapy should be reconsidered. Patients with steroid-refractory GVHD should be enrolled in clinical study until there are data to support a standard salvage therapy.

Weekly paclitaxel as first-line chemotherapy and trastuzumab in patients with advanced breast cancer: A Hellenic Cooperative Oncology Group phase II study

To evaluate the activity and acute toxicity of the combination of weekly paclitaxel as first-line chemotherapy and trastuzumab, in patients with HER-2/neu overexpressing advanced breast cancer (ABC). Weekly paclitaxel has been shown to be a well tolerated treatment with considerable activity in patients with ABC. Clinical trials with transtuzumab, a humanized anti-p185 HER-2/neu monoclonal antibody have demonstrated that this agent produces objective responses in patients with ABC. From December 1998 to April 2000, 34 patients with HER-2/neu overexpressing ABC were treated with weekly paclitaxel; given by one-hour infusion at a dose of 90 mg/m2 immediately followed by trastuzumab, 4 mg/kg as a loading dose and 2 mg/kg i.v. given over 30 min, thereafter weekly for at least 12 weeks. Expression of HER-2/neu was determined by immunohistochemical analysis on fixed, paraffin-embedded tissues. Eligible patients were required to have > or = 25% stained tumor cells. Thirty-three patients completed at least 12 weeks of combined treatment. After completion of the 12th week of treatment, four patients (12%) achieved complete and 17 (50%) partial response. Median duration of response was 11.6 months. More frequent side effects included anemia (56%). neutropenia (27%), peripheral neuropathy (78%), diarrhea (30%), alopecia (70%), arthralgias/myalgias (62%), fatigue (59%) and hypersensitivity reactions (62%). Median time to progression was nine months while median survival had not been reached The combination of weekly paclitaxel and trastuzumab is a safe and active regimen for patients with HER-2/neu overexpressing ABC. Randomized phase III studies with this combination are warranted.

Molecular Analysis and Therapeutic Application. Molecular Targeting for Breast Cancer Treatment.

Advanced biotechnologies have provided benefits to detect a variety of cellular molecules for tumor diagnosis, determination of malignancy, and prognosis of cancers. Improved understanding of the molecular basis of cancers will lead to molecular targeted approaches to cancer prevention and treatment. Monoclonal antibody−based therapeutics targeting cell surface receptor such as HER2/neu/c−erbB2 oncoprotein on breast cancer cells has shown efficacy in clinical trials. HER2 pro−oncogene is a member of the epidermal growth factor receptor family, and HER2 oncoprotein is a well−characterized predictor of tumor aggressiveness. The overexpression of HER2 has been found in about 25% to 30% of breast cancers and associated with poor prognosis, resistance to hormonal therapy and lack of sensitivity to some adjuvant chemotherapy. The recombinant anti−HER2 monoclonal antibody, trastsuzumab(Herceptin), was evaluated in clinical trials for treatment of HER2−over−expressing metastatic breast cancers. The administration of the trastuzumab has produced an objective response in patients with metastatic breast cancers, suggesting that the trastuzumab will be a new molecular targeting therapeutic agent for patients with HER2−overexpressing cancer. Thus, a test result of HER2 overexpression will be a valid criterion in determining eligibility for the trastsuzumab therapy, and reliable detection of HER2 overexpression is an important prerequisite for the success of the trastsuzumab therapy.

Preoperative radiation therapy for patients with T2-T3 carcinoma of the middle-to-lower rectum.

The aim of this study was to determine the effects of preoperative radiation therapy (RT) on the objective responses of patients with rectal carcinoma to their treatment. These effects were assessed with endorectal ultrasound (EUS) evaluation, histopathologic grading of postirradiation tumor mass reduction in the surgical specimen, and analysis of local and distant recurrences. Fifty-nine consecutive patients with palpable adenocarcinoma of the rectum, classified by EUS examination as uT2-uT3 (which meant involvement of the muscular layer and the perirectal adipose tissue, respectively), received 45 grays (Gy) over 3 weeks (2 fractions per day of 1.5 Gy each) given as photons supplied through a high-energy linear accelerator (18 MeV) through 3 fields: 1 posterior and 2 opposed lateral. Surgery was scheduled 2-3 weeks after the end of RT and included a sphincter-saving resection (39 patients) and an abdominoperineal resection (20 patients). Greatest tumor dimension, which was evaluated with rectal endoscopy before RT and measurement of the lesion in the fresh specimen, showed a decrease among two-thirds of the patients; the decrease amounted to approximately one-third of the initial measurement. An echoendoscopic downstaging of the T component was observed among 24.5% of the patients. Complete tumor regression occurred in 8.5% of patients, whereas in 69% only the presence of rare residual cancer cells and prominent fibrosis were found at the pathologic examination of the specimen. Finally, the tumor regressed to pT0 and pT1 in 13.6% of the patients. The overall and disease free 2-year survival rates were 94.0% and 73.7%, respectively, for pT2 and pT3 patients, and 100% for those whose tumors regressed to pT0-pT1 after a median follow-up of 2 years. Hyperfractionated preoperative RT appears to be efficient in achieving tumor shrinkage and destroying the tumor. In this study, the subset of patients with a good response to RT therapy had an excellent clinical outcome at the time of a 2-year follow-up.

Developing recombinant and synthetic vaccines for the treatment of melanoma.

To develop new vaccines for the treatment of patients with cancer, target antigens presented on tumor cell surfaces have been cloned. Many of these antigens are non-mutated differentiation antigens and are expressed by virtually all melanomas, making them attractive components for a widely efficacious melanoma vaccine. These antigens are also expressed by melanocytes, however, and are likely to be subject to immune tolerance. A central challenge for tumor immunologists has thus been the breaking of tolerance to cancer antigens. We review recent clinical trials using experimental cancer vaccines, including recent evidence that therapeutic vaccines can induce objective responses in patients with metastatic malignant melanoma. We focus on the foundations of these approaches in new experimental animal models designed to test novel vaccines and report on what these new models predict for the future development of therapeutic vaccines for cancer.

Tyrosine kinase: implications en pathologie tumorale et perspectives thérapeutiques

The tyrosine kinase family includes growth factor receptor and cytoplasmic enzymes. It plays a key role in normal cell division and abnormal cell proliferation and differentiation. The most common tyrosine kinases are the epidermal-growth factor (EGFR) and platelet-derived growth factor (PDGF) receptors, and a chromosome Philadelphia product, the Bcr-abl oncogene. Many studies have attempted to correlate clinical evolution of tumors with tyrosine kinase expression. However, clinical application of these new prognostic factors has not yet been demonstrated. More recently, tyrosine-phosphorylation inhibitors (tryphostin) have been developed in phase I studies. Results that were obtained show some objective responses in patients with glioblastoma and polymetastatic cancer. Another approach to block tyrosine kinase expression is the use of monoclonal antibodies. Trials using such antibodies have shown interesting preliminary results.

A phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors. A Southwest Oncology Group Study.

A prospective Phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors was conducted by the Southwest Oncology Group. The therapy included 5-fluorouracil, Adriamycin, cyclophosphamide, and streptozotocin (FAC-S) or the same combination without Adriamycin (FC-S) in patients with heart disease. Seventy-four patients were entered and two were ineligible. Sixty-nine of the 72 were histologically reviewed. Six patients were declared ineligible after this review. Fifty-six patients received FAC-S, and nine received FC-S (one patient was inevaluable). The response rates were 31% and 22%, respectively. The median survival of all patients was 10.8 months. The analyses of various clinical and histologic parameters indicated that responses were more common in patients with gastrintestinal carcinoids; there was also a tendency toward shorter survival in patients with tumors that had a higher mitotic rate or the atypical and/or undifferentiated histologic pattern. The FAC-S combination can produce objective responses in patients with metastatic carcinoid tumors, but these are generally partial and brief. It was also concluded that currently available chemotherapy is inadequate.

Adriamycin and bleomycin, alone and in combination, in gynecologic cancers.

Treatment with adriamycin (ADM) and bleomycin (BLEO) alone and in combination has been evaluated in 56 patients with a variety of advanced stage gynecologic cancers. ADM has a high degree of antitumor activity against uterine sarcomas (leiomyosarcoma and stromal sarcoma) and some of the unusual ovarian cancers including ovarian teratoma. ADM was also active and gave clinically worthwhile responses against squamous cell carcinoma of the cervix and vagina. Occasional objective remissions were seen in patients with epithelial ovarian adenocarcinomas. The combination of ADM plus BLEO appeared to show no enhancement of the effect achieved by ADM alone. There were no objective responses in patients with squamous cell carcinoma of the cervix treated with BLEO alone. The usual toxic manifestations of ADM and BLEO were observed, and there appeared to be no potentiation of the toxicity of each agent when used in combination. It is concluded that ADM is a valuable chemotherapeutic agent for certain gynecologic cancers which are usually refractory to other chemotherapeutic agents. Further investigation of its use alone and in combination with other drugs is indicated.