Checking lymph nodes during surgery and assessing the hormone status of tumours could help improve breast cancer survival in the UK, according to research published today in Annals of Oncology.

In a study of over 9,000 breast cancer patients* at 10 hospitals in the East of England researchers found that hospitals with a better average survival were those where surgeons checked lymph nodes during surgery in more than 90 per cent of patients.

Professor Stephen Duffy, Cancer Research UK professor of screening and study author, said: “We found that the proportion of women under 70 who had lymph node checks as recommended by NICE ranged from 81 per cent to 94 per cent with the hospitals with higher percentages having better survival.”

The study also found that, for women over 70, having surgery to remove their tumour and checking the hormone type were the two main factors which explained survival differences between hospitals.

The hospitals showing better survival in the over 70s were those which assessed the hormone receptor status in more of their patients.

The team of researchers** from London and Cambridge compared breast cancer survival rates between 10 different hospitals across eastern England.

For women under 70 the five year relative survival rates ranged from 85 to 90 per cent. And for those over 70 the survival rate was between 65 and 75 per cent.***

The figures are close to the highest rates in Europe**** but the researchers believe that survival could be even better if all hospitals closely followed the existing surgical guidelines.

Professor Duffy continued: “Although survival rates for breast cancer are very good in hospitals we studied in the East of England, rivalling the best in Europe, we have found that there is still room for improvement.

“One reason why survival varied between the hospitals for women under 70 was whether they had their lymph nodes removed and examined. Another is screening as we know from previous studies that women have a much better chance of survival if their tumour is picked up at an early stage. We would encourage all women to attend screening when invited.”

The researchers also found that more women older than 70 are surviving the disease if they have surgery. Another important factor for this group of women was whether the cancer’s hormone type was assessed at diagnosis. The researchers believe that with more hospitals following the guidelines on hormone receptor typing, there would be further improvements in survival.

Professor Gordon Wishart, the leading author on the study said: “Lymph node staging and hormone receptor typing give valuable information to decide on optimal treatment after surgery. As more hospitals follow current professional guidelines and carry out these investigations, more effective treatment will follow and patient survival is likely to improve even further.”

Professor Peter Johnson, Cancer Research UK’s chief clinician, said: “It’s very encouraging to see that at their best, results from the UK are the equal of those in Europe. The real challenge is to make sure that consistently high standards are met in all hospitals, so that every patient can benefit from the significant improvements in survival we have made.”

Notes

*All women had been diagnosed with breast cancer between 1999 and 2003.

**The team of researchers included Dr Clement Brown of the Eastern Cancer Registration and Information Centre and Professor Gordon Wishart, the lead author on the study.

***These figures are relative survival rates calculated from overall rates in the paper.

****Figures compared to the Eurocare study Comparative cancer survival information in Europe. Eur J Cancer. 2009 Apr;45(6):901-8.

Source
Cancer Research UK

Scientists in Michigan and California are reporting an advance toward development of a new generation of drugs that treat disease by orchestrating how genes in the body produce proteins involved in arthritis, cancer and a range of other disorders. Acting like an “on-off switch,” the medications might ratchet up the production of proteins in genes working at abnormally low levels or shut off genes producing an abnormal protein linked to disease. Their report is in the current issue of ACS Chemical Biology, a monthly journal.

In the study, Anna K. Mapp and colleagues discusses molecules that cause genes to be active and churn out proteins - so-called transcriptional activators. That’s because they control a key process known as transcription, in which instructions coded in genes produce proteins. Malfunctions in these activators could lead to altered transcription patterns that lead to disease. For example, variations in the tumor suppressor gene p53 are found in more than half of all human cancers.

Mapp describes discovery of a group of molecules that could be used to help scientists better understand transcription. Known as activator artificial transcriptional activation domains, these small molecules mimic natural activators and could provide insights on how mistakes in gene regulation result in various diseases. “Evidence suggests that these small molecules mimic the function and mechanism of their natural counterparts and present a framework for the broader development of small molecule transcriptional switches,” Mapp states.

Article:
“Amphipathic Small Molecules Mimic the Binding Mode and Function of Endogenous Transcription Factors”
http://pubs.acs.org/stoken/presspac/presspac/full/10.1021/cb900028j

Contact:
Anna K. Mapp, Ph.D.
University of Michigan
Ann Arbor, Mich.

Source:
Michael Woods

American Chemical Society

Proteolix, Inc. announced data from ongoing Phase 2 and Phase 1b clinical trials of carfilzomib for the treatment of multiple myeloma at the 14th Congress of the European Hematology Association (EHA) in Berlin, Germany. Carfilzomib is the first in a new class of selective, irreversible proteasome inhibitors being developed by Proteolix for the treatment of hematologic malignancies and solid tumors.

Relapsed Multiple Myeloma Patients Achieve Responses with Single-Agent Carfilzomib

Keith Stewart, M.B., Ch.B., Professor, Division of Hematology/Oncology at the Mayo Clinic, Arizona presented positive data from an ongoing Phase 2 clinical trial of single-agent carfilzomib in relapsed multiple myeloma patients. Patients in the study have relapsed after receiving one to three prior therapies and are stratified according to prior exposure to bortezomib.

A total of 31 patients have been enrolled in the Phase 2 clinical trial to date, of which 45 percent had no prior bortezomib experience and 55 percent relapsed following bortezomib treatment. In both arms, substantial response rates were achieved and sustained. Bortezomib-naive patients achieved an overall response rate of 57 percent with a median duration of response of 8.5 months. The median time to progression in this cohort has not been reached.

Among patients with prior bortezomib exposure, 18 percent achieved partial responses and the median duration of response has not yet been reached in this population. The median time to progression for patients in this cohort was 8.9 months. Ten additional patients achieved stable disease.

“Carfilzomib monotherapy achieves durable responses in relapsed multiple myeloma patients regardless of their prior exposure to bortezomib, and notably, a number of patients remain progression free after twelve cycles,” said Dr. Stewart. “Further, carfilzomib has been generally well tolerated, and the compound’s selectivity appears to avoid the off-target effects, such as peripheral neuropathy, associated with currently available proteasome inhibitors.”

Adverse events were generally mild and manageable and carfilzomib has been well tolerated for up to one year. Of 31 patients treated, 29 percent have received 12 full cycles of treatment.

These data were reported by Dr. Stewart in an oral presentation, titled “# 0474: Safety and Efficacy Update of PX-171-004, an Open-label Phase II Trial of Carfilzomib in Relapsed Multiple Myeloma,” on Saturday, June 6, 2009.

Carfilzomib Combination with Lenalidomide is Well-Tolerated; Achieves Responses in Heavily Pre-treated Patients at Low Doses

Positive preliminary data from an ongoing Phase 1b dose-escalating trial of carfilzomib in combination with lenalidomide and low-dose dexamethasone in relapsed and refractory patients was presented by Michael Wang, M.D., of the University of Texas MD Anderson Cancer Center on Sunday, June 7, 2009. The Phase 1b clinical trial is designed to evaluate safety and to establish a maximum-tolerated dose of carfilzomib in combination with lenalidomide and dexamethasone administered on a 28-day treatment cycle. Lenalidomide in combination with dexamethasone is currently indicated for use in patients with multiple myeloma who have had at least one prior therapy.

To date, the combination of carfilzomib and lenalidomide was well tolerated in heavily pre-treated patients and adverse events were manageable. The most common adverse events reported include anemia and fatigue. No cases of peripheral neuropathy, a common adverse event associated with approved proteasome inhibitors, have been reported. A maximum-tolerated dose has not yet been established and dose-escalation in this trial continues.

Sixty-one percent of the 18 patients evaluable for efficacy achieved very good partial, partial or minor responses. Responses occurred in the first 28-day cycle of treatment at doses well below the maximum-tolerated dose for either lenalidomide or carfilzomib alone. Initial responses improved with continued therapy. Potent inhibition of the proteasome has been observed and the lenalidomide/dexamethasone combination does not appear to interfere with carfilzomib’s activity.

“Results observed to date in our Phase 1b combination study of carfilzomib are very promising,” said Michael Kauffman, M.D., Ph.D., Chief Medical Officer of Proteolix. “We believe that carfilzomib in combination with lenalidomide and dexamethasone should provide superior activity to lenalidomide and dexamethasone alone. In addition, the lack of overlapping toxicities and absence of peripheral neuropathy may allow for long-term dosing - and ultimately, sustained clinical benefit.”

Dr. Wang presented interim data from the Phase 1b clinical trial during the Novel Therapeutics and Drug Resistance session in an oral talk, titled “#1070: PX-171-006: Phase IB Multicenter Dose Escalation Study of Carfilzomib (CFZ) plus Lenalidomide (LEN) and Low Dose Dexamethasone (LODEX) in Relapsed and Refractory Multiple Myeloma (MM) - Preliminary Results.”

About Multiple Myeloma

According to the American Cancer Society, in 2009, approximately 20,500 new cases of multiple myeloma will be diagnosed in the United States. Newly diagnosed patients have treatment options that include combination chemotherapeutic agents and stem cell transplantation. While many patients respond to treatment, most eventually relapse and require subsequent treatment. Few patients are ultimately cured of their disease. In spite of advances in the treatment of multiple myeloma, this year alone, approximately 10,500 patients are expected to die of the disease.

About Carfilzomib

Carfilzomib is the first in a new class of selective, irreversible proteasome inhibitors. Carfilzomib produces specific and sustained inhibition of the proteasome, leading to apoptosis in cancer cells with minimal off-target effects. In Phase 1 and Phase 2 clinical trials, carfilzomib has demonstrated single-agent activity in hematologic malignancies and solid tumors, including multiple myeloma, Waldenstrom’s macroglobulinemia, mantle cell lymphoma and renal cell carcinoma.

Proteolix is conducting a comprehensive clinical development program evaluating carfilzomib for the treatment of multiple myeloma, including an ongoing accelerated approval study in heavily pre-treated relapsed/refractory patients and a Phase 2 clinical trial in relapsed patients stratified by prior treatment with bortezomib. Both Phase 2 clinical trials are being conducted by Proteolix in collaboration with the Multiple Myeloma Research Consortium (MMRC). A Phase Ib clinical trial of carfilzomib in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma is also ongoing. In addition, Proteolix is conducting a single-agent Phase 2 clinical trial of carfilzomib in patients with recurrent or advanced solid tumors.

About Proteolix

Founded in December 2003, Proteolix, Inc. is a privately-held biotechnology company, headquartered in South San Francisco, dedicated to discovering, developing and commercializing novel therapeutics that target protein degradation pathways for cancer and autoimmune diseases. Proteolix’s lead product, carfilzomib, is the first in a new class of selective, irreversible proteasome inhibitors. Proteolix is also developing a pipeline of novel proteasome inhibitors, including a selective, oral proteasome inhibitor and a selective immunoproteasome inhibitor.

Source: Proteolix, Inc