Breast Cancer Research Update

EARLY STAGE BREAST CANCER – A RESEARCH UPDATE

Words – Ian Campbell and Jenni Scarlet



Every year sees the publication of large volumes of research relating to breast cancer. The following is a summary of some of the studies that New Zealand women have been, or will be, involved with. They reflect the heterogenous or varied nature of breast cancer and the need for women (and men) diagnosed with breast cancer to have personalised care and treatment tailored to their particular type of breast cancer.

Effect of menstrual cycle on survival from breast cancer
Controversy regarding a possible link between the menstrual cycle phase (follicular or luteal) at the time of surgery for breast cancer and the outcome has existed for several decades. A majority of past information on the menstrual phase has been obtained from research that looked back at the charted documentation of a woman's last menstrual period. However, this approach is fraught with errors. A large international collaborative study where the menstrual phase was determined by the measuring of hormonal levels in blood samples taken within one day of surgery has finally put this issue to rest. Over six years of follow-up results to date show there is no relationship between a recurrence or overall survival and timing of surgery on the basis of the menstrual cycle phase for pre-menopuasal (still having periods) women with early-stage breast cancer - so younger women (and their surgeons) can put their minds at rest over this issue.

New information from the aromatase inhibitor trials for early breast cancer
Tamoxifen has been used to treat early, hormone-sensitive breast cancer for some 30 years. We have previously written in pink magazine about a newer type of anti-oestrogen treatment - aromatase inhibitors (AI’s) which have been tested in women with hormonally sensitive breast cancer (the most common type). AI’s are only effective in post-menopausal women where they block the production of the female hormone oestrogen. There are a number of large international clinical trials that have compared tamoxifen with the AI drugs - anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin). The first overview or review of all worldwide AI trials was presented at a large international breast cancer conference in San Antonio (United States) in December, 2008. This showed that overall AI’s are more effective and safer than tamoxifen in each setting in which they were tested - initial treatment after diagnosis and surgery (anastrozole and letrozole) or being commenced after an initial treatment period of two to three years of tamoxifen (exemestane). The overview has, for the first time, shown an overall survival as well as a recurrence free survival benefit for AI’s. It must be noted that tamoxifen currently remains an important and effective treatment for some women (e.g. pre-menopausal women) and also men.

Optimal sequencing of Letrozole and Tamoxifen
Previously we did not know whether it was better to start with an AI soon after diagnosis and to continue for five years; or if giving both drugs in a sequence (letrozole followed by tamoxifen or tamoxifen followed by letrozole) would show superior results. Further results from the Breast International Group (BIG-98) trial, coordinated through the Australian New Zealand Breast Cancer Trials Group (ANZBCTG) show that it seems to be the most promising strategy to start treatment with letrozole and continue for five years, but if necessary, patients who have particular side effects on letrozole can switch to tamoxifen after two years without any loss of effectiveness.

Study examining the impact of breast cancer treatment on memory and thinking
Most menopausal women diagnosed with hormonally sensitive breast cancer take drug treatments that block or reduce oestrogen production, such as tamoxifen or letrozole. Some women complain of difficulties with memory and thinking, or cognitive functioning, during and after their treatment. This has mostly been attributed to chemotherapy and has been referred to as "chemobrain". Oestogen is known to be important for cognitive functioning. The possible impact of anti-oestrogen drugs requires more investigation. Women (in the above BIG 1-98 trial) taking either tamoxifen or letrozole during their fifth year of treatment completed tests on memory and thinking.

Somewhat to our surprise results showed that women receiving letrozole (which dramatically lowers oestrogen levels) in their fifth year of treatment showed better cognitive function than those taking tamoxifen. Further results are planned in one year’s time to see whether this difference continues after women stop taking the medications at the completion of their five years of hormonal treatment. Results of such a study examining potential side effects of treatment are important for helping women and their doctors weigh up the pros and cons of taking each type of anti-oestrogen treatment.

Breast cancer and bone health
Bone health is important for women who are diagnosed with breast cancer, as all women (particularly post-menopausal women) are at some risk of osteoporosis. AI’s may reduce the density of bone and increase fracture risk in women receiving these drugs.

Trials on women with early breast cancer have shown that adding a drug to protect the bone (called a bisphosponate) improves bone density and reduces the risk of fracture in women with breast cancer. An unexpected finding was that one such drug, called Zoledronate (given six monthly during letrozole treatment), also reduces the risk of breast cancer recurring. A large amount of research continues to be done looking at the anti- cancer effect of bisphosponate drugs.

Treatments for HER2 positive early breast cancer
HER2 is a protein found in high levels in approximately a quarter of all breast cancers. Tumours that overproduce HER2 tend to be more aggressive and more likely to recur than those that are HER2 negative. There are a number of worldwide clinical trials investigating treatments for HER2 positive early breast cancer.

Updated four year follow-up information was released earlier this year from the HERA (the HERceptin Adjuvant) trial, and it has confirmed the value of taking one year of Herceptin to continue to reduce the risk of breast cancer returning in HER2 cancers. Information on the effectiveness of two years of treatment (with Herceptin) is awaited. To date, four large scale clinical trials (including the HERA and two large United States trials) involving over 13,000 women worldwide have demonstrated significant survival benefits for early stage HER2 positive disease when Herceptin is given for a year.

The five year follow-up data from the FinHer trial became available earlier this year and no longer shows a statistically significant benefit with regard to improving breast cancer free and overall survival, meaning there is no longer evidence to support a nine week regimen. The FinHer trial is the small Finnish trial that explored the shorter nine week Herceptin duration.

The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) study continues to enrol women worldwide. The ALTTO trial will be enrolling around 8,000 women in 50 countries over six continents. This research is studying breast cancer outcomes for women either receiving one year of treatment with Herceptin with one year of lapatinib, versus a sequence of both drugs, versus a combination of Herceptin and lapatinib for one year. The medications being tested in ALTTO target HER2 in different ways. Researchers want to find out whether one drug will prove better than the other in helping women live longer without a recurrence of their cancer, or if the two drugs will work better together.

Another trial testing the delayed use of the HER2 (and HER 1) blocking oral tablet lapatinib (Tykerb) will release results in around two years time. The Tykerb Evaluation After ChemotHerapy (TEACH) trial is evaluating the use of lapatinib in women who have finished their chemotherapy treatment for early stage HER 2 positive breast cancer more than 12 weeks previously (and have not received Herceptin).

The Synergism (and Short) Or Long Duration (SOLD) trial comparing the effectiveness of nine weeks Herceptin treatment with twelve months continues to enrol women.

The use of a 21 gene set to predict the value of certain treatment
It is a goal of researchers to be able to more accurately determine which types of breast cancer will respond to each available treatment, and which cancers will not benefit. Some New Zealand women may be participating as soon as next year in an American- based collaborative study called the TAILORx trial. TAILORx stands for "Trial Assigning Individualised Options for Treatment (Rx)” and the purpose of this research is to determine which women with early stage breast cancer would be more likely to benefit from chemotherapy. Standard treatment for women who are eligible for this trial includes chemotherapy and hormonal therapy. Use of a diagnostic test called the "Oncotype DX assay" can more precisely estimate an individual woman's chances of benefitting from chemotherapy in addition to hormonal treatment. This study is aimed at women where the likelihood of benefitting remains uncertain. Use of the Oncotype DX assay may result in more selective use of chemotherapy for those women who are most likely to benefit from it. It may also reduce the need for chemotherapy in women who are unlikely to benefit from it.

Research investigating survivorship issues
More women than ever are surviving their breast cancer and it might be easy for some to assume that life should go back to “normal” when treatment finishes. However, this can remain a challenging time for many women. Some still face side effects from treatment such as lymphoedema, or discomforts from treatment induced menopause. Others are coping with issues of body image after mastectomy, a sense of vulnerability as a result of their cancer diagnosis, or a loss of fertility, relationships, finances and returning to work.

Life after breast cancer is a more recent area of research and is investigating issues resulting from the multiple effects of a breast cancer diagnosis. Two Australian studies were recently presented at the ANZBCTG conference in July on the topic of supportive or survivorship care.

Preliminary Results from Exercise for Health: A Breast Cancer Recovery Project
Past studies looking at exercise after a cancer diagnoses have shown positive outcomes, including improvements in physical function, fitness, quality of life and fatigue. “Exercise for Health” was a project carried out by researchers at the University of Queensland and Queensland University of Technology. The Queensland researchers, along with staff at Queensland’s hospitals, instituted a face-to-face and/or telephone delivered exercise programme to recently diagnosed women (including some women living in rural and remote areas). Exercise was tailored to each woman and the phase of treatment she was undergoing. Participating women exercised four times per week for 45 minutes and exercise mostly involved walking (and other aerobic exercise). Early results suggest an overall improvement in quality of life, and symptoms of anxiety and fatigue. This project will form the basis of a larger trial that will be run through the ANZBCTG, which will investigate the question of whether physical activity improves overall survival as well as quality of life after a breast cancer.

Fear of Cancer Recurrence in Cancer Survivors
Research carried out by the Centre for Medical Psychology at the University of Sydney has confirmed that the fear of cancer recurrence is an issue that breast cancer survivors want help with. This is the real fear that the cancer could return in the same place or in another part of the body. New South Wales women diagnosed with breast cancer between the ages of 29-79 years participated in a study investigating fear of cancer recurrence (FCR). Preliminary findings show that breast cancer patients, particularly younger women (diagnosed 45 years and younger), were vulnerable to FCR relative to other cancers. FCR appears to be associated with greater psychological distress and health service usage. The researchers also concluded that FCR is something that health professionals need to ask survivors about, as it may be amenable to change.

In summary
In New Zealand we have over 25,000 people who have survived their breast cancer. Whilst the length women live free of breast cancer is extending (through measures such early detection and better and more refined medical treatments), future research on survivorship issues will assist in identifying the many aspects of quality of life that may benefit from introducing specific lifestyle changes or other means of supportive or psychological care.