Ethnicity and breast cancer - does it matter?

Breast cancer research needs to evaluate whether a person's ethnicity influences their response to treatment and its outcome, according to researchers at Imperial College London and published in The Lancet online.

Emerging evidence suggests that particular drugs may benefit people from one ethnic group more than others, because of differences in their genetic makeup. Most key trials looking at treatments for breast cancer have been carried out in predominantly caucasian populations in Europe, North America and Australasia.

Other populations might not respond to a drug in the same way as the Caucasian populations in these trials. The researchers suggested that clinical trials should record participants' ethnicity and analyse whether there are differences in how patients from particular ethnic groups respond to a particular therapy.

One example is a drug called Herceptin (trastuzumab), which is commonly used to treat people with breast cancer that is HER-2 positive. Most studies of trastuzumab have not reported the ethnicity of participants. A recent study showed that people with a particular genotype responded better than others to treatment with this drug. The genotype in question is more common in some ethnic groups than in others, so it could be argued that an individual's ethnicity could be a key factor in determining which treatments are most likely to benefit them.

Another research group at the University of Miami, Fl has been looking at whether breast tissue samples from different ethnicities include groups of differentially expressed genes. Gene expression in breast tissue from African-American women differs
from that in Caucasian and Hispanic women, just as gene expression in Hispanic women differs from both African-American and Caucasian women.

In their latest study, Baumbach et al. are focusing on women with “triple-negative” breast cancer. These women are negative for the genes for estrogen receptor (ER), progesterone receptor (PR) and HER2/neu, an epidermal growth factor receptor. This combination is associated with a particularly poor prognosis.

Thee results showed surprising differences in normal tissues; some of the differences were specific to African-Americans and were not found in Hispanics or Caucasians. They tended to have a basal-like phenotype and to have an aggressive form of breast cancer before the age of 50. The research also showed that in considering BRCA1 and BRCA2, while they had a lower incidence of deleterious germline mutations but a higher number of missense mutations. They are now doing real time PCR analyses to see if the biggest differences can be validated and proteomic research will follow in the future, making this a large and very important long term study that may influence treatment paradigms in the future.

Promising new tool for monitoring lung cancer

A non-surgical technique that may help doctors monitor how well non-small cell lung cancer patients are responding to treatment is currently being tested. Using a device known as a CTC-chip to analyze circulating tumour cells from patient's blood samples, it was possible to identify whether patients had genetic mutations that would make them less likely to respond to certain therapies.

The research, published in the New England Journal of Medicine, is still in the early stages. However, if future studies confirm it works, the technique could offer lung cancer patients a non-invasive, safe way to monitor their disease and find out which treatments will work. Currently, in order to get that type of information, patients would have to undergo dangerous, invasive procedures to sample tissues and cells.

The current findings will need to be replicated in larger studies before the chip is used widely, since only 27 patients participated in the pilot study.

The CTC-chip opens up a whole new field of studying tumors in real time. When the device is ready for larger clinical trials, it should provide new ways of measuring treatment response, defining prognostic and predictive measures, and studying the biology of blood-borne metastasis, which is the primary method by which cancer spreads and becomes lethal.

Blood samples from 27 patients, 23 of whom had a cell-surface protein mutation known as the epidermal growth factor receptor (EGFR) mutation were tested. Using the CTC-chip, the researchers were able to identify the mutation from the circulating blood tumour cells 92% of the time.

It was also noticed the chip could detect changes over time. Research has shown that tumours with the EGFR mutation are more likely to respond to a class of drugs known as tyrosine kinase inhibitors, or TKIs; Tarceva (erlotinib) and Iressa (gefitinib) are 2 TKIs used to treat lung cancer. However, the patient's tumours eventually come back. Using the CTC-chip, the researchers found out why; it appears that the tumour cell's genetic makeup evolved over the course of treatment.

Biopsy samples taken at the time of diagnosis can never tell us about changes emerging during therapy or genotypic differences that may occur in different sites of the original tumour, but the CTC-chip offers the promise of noninvasive continuous monitoring.

This information could one day help doctors see when a patient was becoming resistant to treatment so that new therapies could be tried earlier. However, there is still work to do to make this technique more efficient on the larger scale outside of the clinical trial setting.

Will infusing granulocytes cure human cancer?

Scientists at Wake Forest University Baptist Medical Center are about to begin a trial to determine whether a new cancer treatment will be as effective at eradicating cancer in humans as it has proven to be in mice.

The treatment will involve transfusing specific white blood cells, called granulocytes into patients with advanced forms of cancer. A similar treatment using white blood cells from cancer-resistant mice has previously been highly successful, curing 100 percent of lab mice afflicted with advanced malignancies.

Granulocyte - image via WikipediaThe study is being announced on June 28 at the Understanding Aging conference in Los Angeles. It will involve treating cancer patients with white blood cells from healthy young people whose immune systems produce cells with high levels of cancer-fighting activity.

The basis of the study was the discovery of a cancer-resistant mouse and their subsequent finding that white blood cells from that mouse and its offspring cured advanced cancers in ordinary laboratory mice. They have since identified similar cancer-killing activity in the white blood cells of some healthy humans.

Human cancer-fighting cells from healthy donors have been tested against human cervical, prostate and breast cancer cells in the laboratory, with good results. The scientists say the anti-tumor response primarily involves granulocytes of the innate immune system, a system known for fighting off infections.

Granulocytes are the most abundant type of white blood cells and can account for as much as 60 percent of total circulating white blood cells in healthy humans. Donors can give granulocytes specifically without losing other components of blood through a process called apheresis that separates granulocytes and returns other blood components back to donors.

In a small study of human volunteers, it was found that cancer-killing activity in the granulocytes was highest in people under age 50. This activity can be lowered by factors such as winter or emotional stress. They said the key to the success for the new therapy is to transfuse sufficient granulocytes from healthy donors while their cancer-killing activities are at their peak level.

For the upcoming study, 500 local potential donors who are 50 years old or younger and in good health are being recruited to have their blood tested. Of those, 100 volunteers with high cancer-killing activity will be asked to donate white blood cells for the study. Cell recipients will include 22 cancer patients who have solid tumours that either didn't respond originally, or no longer respond, to conventional therapies.

The goal of the phase II study is to determine whether patients can tolerate a sufficient amount of transfused granulocytes for the treatment. Participants will be monitored on a regular basis, and after three months scientists will evaluate whether the treatment results in clear clinical benefits for the patients. If this phase of the study is successful, the study will be expanded to determine if the treatment is best suited to certain types of cancer.

PTLD may help predict lymphatic spread of localized prostate cancer

A recent study published in The Prostate showed that analysing peritumoural lymphatic vessel density (PTLD) in prostate biopsy cores could help to predict the lymphatic spread of clinically localized prostate cancer.

Researchers examined positive biopsy cores from 99 patients who underwent radical prostatectomy, immunostaining them with a monoclonal antibody against lymphatic endothelium. It was found that peritumoural lymphatic vessels were present in at least one positive biopsy core in 90.9 percent of cases, while intratumoral lymphatic vessels were seen in just 23.2 percent of cases.

Positive biopsy core rates were significantly associated with average and maximal PTLD and the presence of intratumoral lymphatic vessels.

This approach may become a useful technique for predicting early spread of the disease and suggests that patients with high PTLD in biopsy specimens should be carefully monitored after surgery.

Are ESA's safe enough for cancer patients?

Earlier this year the FDA held a fourth session with the Oncologic Drugs Advisory Committee (ODAC) to review erythropoietin stimulating agents (ESA's). In 1993, ESA's were approved to reduce the number of red blood cells transfusions in cancer patients who have chemotherapy induced anemia. There is no doubt that the drugs do reduce the number of transfusions. They are also believed to alleviate symptoms such as fatigue and improve quality of life associated with the anemia, although the FDA has said that these remain 'unproven'.

The biggest challenge facing ODAC and the FDA though, is deciding whether ESA's very benefit in anemia is also a negative in terms of increased mortality and/or tumour progression. Eight controlled clinical trials suggest that there is evidence of increased risk of mortality and tumour progression in patients who have head & neck cancer, breast cancer, non-small cell lung cancer (NSCLC) and cervical cancer. According to the FDA, the new studies are either much larger than the original ones used to establish safety of the ESA's or have a different underlying histology.

In addition, the FDA claims that there is insufficient data to rule out mortality, shorter time to progression or lower loco-regional control in cancer other than NSCLC. As a result, FDA have asked ODAC to consider the following options:

- Remove the indication to treat anemia caused by cancer chemotherapy
- Restrict the indication to only patients who will not be cured by treatment intervention and contraindicate in adjuvant therapy
- Restrict use to specific cancer sub-types where safety has been adequately assessed (only NSCLC)
- Contraindicate use where harmful effected have been demonstrated (breast and head & neck cancers)
- Mandate risk management strategies

What is clear is that ESA's do offer a valuable clinical benefit in chemotherapy-induced anemia when used appropriately to avoid transfusions. The question is really one of risk-benefit because the very mechanism by which they work might also induce negative consequences.

It will be interesting to see what happens; The ESA market is worth several billion a year and sales are likely dropping with the repeated FDA discussions about risk benefit and safety.

Magnets in cancer treatments - a new oncology tool or a bad idea?

Biopsy results can be ambiguous: sometimes they can be negative simply because there are too few malignant cells in the sample to be detected - not because all trace of disease has gone. Researchers from the University of New Mexico and the company Senior Scientific, both in Albuquerque, have devised a solution that harnesses the power of magnetic attraction.

The idea is to use magnetic iron oxide nanoparticles encased in a biocompatible material. These in turn can be coated with antibodies that bind to chemicals found only in cancerous cells. When injected into the body, thousands of the particles stick to cancer cells, turning them into miniature magnets. The cells can then be drawn towards magnets encased in the tip of a biopsy needle (Source: Physics in Medicine and Biology, vol 52, p 4009).

A mathematical model of the system confirmed that significant numbers of cancer cells, laden with nanoparticles, could be attracted to a needle within two or three minutes. In the lab, the researchers showed that a magnetised needle could attract leukemia cells surrounded by nanoparticles and suspended in blood or other synthetic materials designed to mimic bodily fluids. Nanoparticles have been used before to destroy diseased cells, but this was the first time they actually retrieved cells.

More recently, researchers have been wondering if cancer treatments be enhanced by something as simple as a magnet. A promising way to tackle some diseases is to deliver cells with modified genes to diseased tissue. Getting enough of the modified cells to the affected area can be tricky.

Claire Lewis and colleagues from the University of Sheffield inserted magnetic nanoparticles, as well as cancer-fighting genes, into monocytes, the white blood cells commonly used in gene therapy, and injected them into mice with tumours. A magnet placed above the tumour caused the cancer-fighting monocytes to congregate there (Source: Gene Therapy, DOI: 10.1038/gt.2008.57).