Friday, August 13, 2010
Technique to Preserve Fertility in Young Women May Be Unsafe for Patients With Leukemia (AML/CML)-- press release
Note: study of 18 patients (AML/CML)
WASHINGTON, Aug. 13 /PRNewswire-USNewswire/ --
Although the use of ovarian tissue cryopreservation and transplantation has lead to 13 live births in women with lymphoma or solid tumors, this method of fertility preservation may be unsafe for patients with leukemia, according to a recent study published online in article: Blood, the journal of the American Society of Hematology "Reimplantation of cryopreserved ovarian tissue from patients with acute lymphoblastic leukemia is potentially unsafe". The method involves removing and freezing ovarian tissue before the patient undergoes aggressive chemotherapy and radiotherapy, and then reimplanting the tissue once the cancer has been brought under control. One major concern with leukemia patients is the risk that their frozen-thawed ovarian tissue might harbor malignant cells that could induce a recurrence of the disease after reimplantation.
"Our study provides clear evidence that cancer cells in women with acute and chronic leukemias can contaminate the ovaries," said Marie-Madeleine Dolmans, MD, professor at the Universite Catholique de Louvain in Brussels and lead author of the study. "If this tissue is reimplanted in these women when they're ready to have children, there's a good possibility that the cancer will come back." ...cont'd
"Moreover, chemotherapy before ovarian cryopreservation does not exclude malignant contamination. Finally, reimplantation of cryopreserved ovarian tissue from ALL and CML patients puts them at risk of disease recurrence."
Take home message: There are extensive preclinical studies with transformed cells in culture and tumor-bearing animal models, as well as limited clinical studies reported to date, which indicate that HDAC inhibitors will be most useful when used in combination with cytotoxic or other targeted anticancer agents.
Note: having been involved in WHO's (World Health Organization) Patients for Patient Safety I had the ocassion several times to hear Don Berwick speak. Here are some notes from Trisha's blog:By Trisha Torrey, Patient Empowerment Guide
Patient Empowerment Blog
Patient Empowerment Blog
Here's an example of Dr. Berwick's point of view. From the IHI website, this is the No Needless List:
No needless deaths
No needless pain or suffering
No helplessness in those served or serving
No unwanted waiting
No one left out
Assessing Women at High Risk of Breast Cancer: A Review of Risk Assessment Models: Abstract and Introduction
".......In addition to increasing the risks of breast and ovarian cancers, germline mutations in BRCA1 and BRCA2 are associated with an increased risk of prostate cancer and BRCA2 mutations are associated with increased risks of pancreatic and gastric cancers and melanoma. BRCA mutations tend to cluster within certain ethnic groups, such as Ashkenazi Jews,[13–15] and in some populations, such as those in the Netherlands, Iceland,[17,18] and Sweden. Germline mutations that are associated with familial breast cancer have been identified in other genes, including TP53, PTEN, ATM, CHEK2, NBS1, RAD50, BRIP, and PALB2, and others are suspected.[20,21]"
Women who are at high risk of breast cancer can be offered more intensive surveillance or prophylactic measures, such as surgery or chemoprevention. Central to decisions regarding the level of prevention is accurate and individualized risk assessment. This review aims to distill the diverse literature and provide practicing clinicians with an overview of the available risk assessment methods. Risk assessments fall into two groups: the risk of carrying a mutation in a high-risk gene such as BRCA1 or BRCA2 and the risk of developing breast cancer with or without such a mutation. Knowledge of breast cancer risks, taken together with the risks and benefits of the intervention, is needed to choose an appropriate disease management strategy. A number of models have been developed for assessing these risks, but independent validation of such models has produced variable results. Some models are able to predict both mutation carriage risks and breast cancer risk; however, to date, all are limited by only moderate discriminatory accuracy. Further improvements in the knowledge of how to best integrate both new risk factors and newly discovered genetic variants into these models will allow clinicians to more accurately determine which women are most likely to develop breast cancer. These steady and incremental improvements in models will need to undergo revalidation....cont'd
Note: references studies - WHI (Women's Health Initiative) and California Teachers Study
Clinicians vary in their approaches to HT, said Dr. Ursin. "Certain gynecologists are very careful with finding the right dose for each woman, and some even prescribe [estrogen] alone for women who have a uterus, but then monitor the uterus carefully. Please keep in mind that the risk of breast cancer associated with EPT is relatively moderate. The risk of endometrial cancer with [estrogen] alone is much higher — a more than 4-fold increase in risk in this same population of California teachers," she said.
Note: cell 'lines' (test tube) vs patient tumors
"....But with all the effort and money being put into pharmacogenomics research using cancer cell lines, it is appropriate to ask: how faithfully do cancer cell lines represent the tumors that they are being used to model?"
"Next, do cancer cell lines behave similarly to the tumors they are intended to model to be useful for pharmacogenomics research? First, cancer cell lines are more appropriate for assessing the response to cytotoxic anticancer drugs, rather than the response to newer biologic agents which exert their anti-tumor effects via mechanisms other than eliciting cell death. Second, an important consideration to keep in mind when using cancer cell lines for pharmacogenomics research is that cell lines are generally more sensitive to cytotoxic agents than solid tumors.
"Another important question is: how well does testing in cancer cell lines predict responses in clinical trials with real world patients? When assessing whether there is a correlation between drug activity in Phase II clinical trials and preclinical activity in cancer cell line models, one study found that preclinical activity did not correlate with Phase II response, with the exception of non-small-cell lung cancer .
However, ..........It is becoming more and more apparent that the process of culturing cells in vitro alters the genetic make-up of the cancer cell lines."
Note: Correspondence (in full), still early days in research but progress noted
"In an article just published in Genome Biology, Steven Jones and colleagues at the British Columbia Cancer Agency have used next generation sequencing to monitor the development of a tumor as it metastasized and used the genomic information to inform treatment.
Cancers are known to accumulate mutations as they progress, and there are several mutations characteristic of metastases. However, even the most well-characterised of tumor types show genetic heterogeneity, and there are few data available for rare tumor types. The recent advent of next generation sequencing technology, allowing rapid and inexpensive genome sequencing, has made it possible to explore the genomic landscape of tumors in more detail.
In this study, a man presented with an unusual cancer of the tongue. He received surgery and radiotherapy, but was subsequently found to have metastases in the lungs. The patient was initially treated with the EGFR inhibitor erlotinib, but the lung metastases continued to grow. Sequencing of the metastases uncovered amplification of the RET oncogene, which explained the resistance to erlotinib, and also suggested the use of the RET inhibitor sunitinib. This drug reduced the size of the lung lesions for a few months, before they started to grow again. A skin metastasis was also detected, and sequencing uncovered seven new mutations that were present in neither the lung metastases nor the original tongue tumor. It appeared that the tumor had upregulated the AKT signalling pathway to compensate for the inhibition of the RET pathway.
This eloquent study demonstrates nicely both how tumors respond to treatment with compensatory changes and also how genomics can be used to guide medical treatment.