Breast Cancer: Advances in Diagnosis & Treatment

INTRODUCTION
The past year has seen significant forward movement in the breast cancer field. It is very exciting to see high-quality research on alternative medicine techniques as well as allopathic (conventional) ones.

Currently, chemotherapy is a vital part of allopathic breast cancer treatment, for both primary and metastatic disease. As advances in chemotherapy are thoroughly covered in other publications, I will instead focus on non-chemotherapy advances in this article.

This year, I have seen new research giving us more information about which herbs, supplements, and other alternative/complementary approaches can minimize treatment side effects and possibly even reduce the risk of breast cancer recurrence. Other progress has improved our ability to determine the full extent of a primary breast cancer, making possible better surgical planning. Finally, I have seen broader acceptance of tests allowing women less likely to benefit from chemotherapy to forgo it with confidence.

ANTIOXIDANTS & CHEMOTHERAPY
An excellent article by Dr. Keith Block reviewed 845 studies, discarding all those that were not randomized or controlled.1 The remaining 19 studies showed that antioxidants such as glutathione, melatonin, vitamin A, vitamin E, vitamin C, ellagic acid (from raspberries, strawberries, and cranberries), and N-acetyl cysteine did not adversely affect the outcome of patients who were also on chemotherapy. In fact, these patients had improvements in their survival time, tumor responses, or both.

As more highquality studies are published, I hope to see more oncologists using antioxidants with chemotherapy.

BOSWELLIA USE IN BRAIN METASTASES
Last year, Dr. Dana Flavin at the Foundation for Collaborative Medicine and Research in Greenwich, CT, reported on a remarkable case of a woman with breast cancer whose multiple brain metastases showed no improvement after two weeks of Xeloda and brain radiation.2 She was then started on boswellia 800 mg three times a day. (Boswellia, also known as Indian frankincense, is an herbal supplement with anti-inflammatory properties and is generally available through retail and online health food stores.) Ten weeks later, a repeat brain CT showed complete resolution of the brain metastases. Impressively, she has been maintained on boswellia for the past four years with no recurrent brain metastasis.

Subsequently, Dr. Flavin has had two more women with brain metastases greatly improve using the same regimen. Reportedly, Harvard’s Dana Farber Cancer Center is seeking approval for a clinical trial to study boswellia use in this setting.

NUTRITION CONTROVERSIES
The December 2006 San Antonio Breast Cancer Symposium (SABCS) saw the unveiling of the Women’s Intervention Nutrition Study (WINS), a large randomized, controlled trial that compared breast cancer patients on high-fat and low-fat diets.3 This study was a joint effort by several institutions including Beth Israel Deaconess Hospital, Memorial Sloan-Kettering Cancer Center, and the University of California, Los Angeles. They found a substantial survival benefit in the low-fat group, especially for those with estrogen receptor-negative cancer.

In contrast, the Women’s Healthy Eating and Living (WHEL) study published recently by the University of California at San Diego showed no survival advantage of a high vegetable/fruit, low-fat, and high-fiber diet.4 Although this trial was also large, randomized, and controlled, it had two key differences from WINS: first, the low-fat group in the WHEL study had, on average, a much higher daily fat intake than those in WINS (45 grams versus 33 grams). Second, the women in the WHEL study gained weight as opposed to those in WINS who shed pounds. Since a Mayo Clinic study showed that breast cancer survivors who gain weight have reduced survival, it is quite possible that whatever benefit the WHEL participants derived from the relatively low-fat and high vegetable/fruit intake was neutralized by their weight gain.5

Interestingly, the same group who published the WHEL study joined Stanford, the Northern California Kaiser Permanente group, and others in a large multi-institutional clinical trial. They found that when women with breast cancer combine higher vegetable-fruit consumption with increased physical activity, their chances of surviving increased by nearly 50%, regardless of their level of obesity.6

PSYCHOSPIRITUAL ASPECT OF BREAST CANCER
An interesting study out of Baylor College of Medicine noted that women who blamed themselves for their breast cancer and lacked self-forgiveness reported more mood disturbances and a lower quality of life.7

Another report in the Journal of the National Cancer Institute showed that breast cancer survivors, particularly African-Americans, have a higher rate of suicide than the rest of the population.8

These studies point to the importance of psychological health and reinforce the fact that a proactive approach to emotional issues is a key part of an integrative breast cancer treatment program.

ALTERNATIVE APPROACHES
There are various alternative approaches that have shown to be beneficial in recent studies:

» Aromatherapy massage was shown to reduce anxiety and depression.9
» Yoga improved sleep, physical function, and possibly also fatigue in women getting radiation therapy.10
» Reiki, an energy-based healing system from Japan, improved fatigue in cancer patients.11
» Mayo Clinic research suggests that American ginseng at 1000 to 2000 mg per day may be effective for alleviating cancer-related fatigue.12
» A Columbia University study showed that acupuncture can reduce the joint pains caused by aromatase inhibitors such as Femara and Arimidex.13
» Eight weeks of aerobic exercise was shown to improve depression and fatigue as well as improve physical conditioning in breast cancer survivors.14
» I was intrigued by Duke University’s report that women taking calcium supplements had more hot flashes that those who did not. This small study was presented at the ACSO Breast Cancer Symposium two weeks ago. It remains to be seen whether this relationship holds up under larger, more rigorous studies.15

BREAST MRI
Breast MRI continues to be an area of active research. It is well documented that up to 15% of breast cancers are missed by mammogram and breast ultrasound.16 MRI will catch most of these.

Despite this obvious advantage, MRI is not yet ready to replace mammography as our standard screening tool as it does have a significant false-positive rate. In other words, it is very good at finding even tiny breast lumps, but it cannot always distinguish a benign lump from a malignant one.

Nevertheless, one group of women were found to be excellent candidates for MRI breast screening: those with a high risk of developing breast cancer within five years. Women with BRCA gene mutations fall into this category. In addition, women who have a 20% or greater lifetime risk of breast cancer also fall into this group. One easy way to estimate one’s risk is to use the Gail risk model, an interactive computer program where inputting specific information such as age and family history of breast cancer yields an estimate of both 5-year and lifetime risk of breast cancer. It can be accessed at the National Cancer Institute website: www.cancer.gov/bcrisktool.

For those who have already been diagnosed with breast cancer, a breast MRI can add to the information provided by the mammogram to help plan a surgery that will be sure to remove all of the cancer. In fact, researchers have shown that in at least 16% of women, a preoperative MRI found a second cancer that the mammogram had missed and that would probably have escaped the planned lumpectomy.17 In another study, MRI findings resulted in a change in surgical plans in 15% to 30% of cases.18,19

Additionally, a small study from New York University was just presented at the ASCO Breast Cancer Symposium, showing that women who had preoperative MRI not only tended to have a lower rate of re-excision and improved surgical margins, but also had fewer mastectomies.20  I am now beginning to see breast surgeons who routinely incorporate MRI in their pre-operative protocol.

Unfortunately, this research is not mature enough to say definitively whether preoperative breast MRI is beneficial.  In the meantime, those women who would rather risk a negative (i.e. unnecessary) biopsy than a potentially incompletely excised cancer should talk to their breast surgeons about an MRI.

It is important to note that there are currently no national standards for breast MRI imaging as there are for mammograms. Therefore, it makes sense to have your MRI done at a center that uses dedicated breast MRI coils and whose radiologists have at least three years of experience interpreting them.

GENE EXPRESSION PROFILING
I am very happy to report steady advances in the realm of personalized treatment. For many years, women with lymph node-negative, early stage breast cancer were encouraged to undergo chemotherapy even though only 2% of those over 50 years of age, and only 7% of those under 50, would be expected to benefit from it.21 (Although the percentage of women with early stage breast cancer being saved by chemotherapy seems small, when multiplied by the hundreds of thousands of women diagnosed, it actually translates into thousands more women surviving their breast cancer each year.) The problem is that you have to give chemotherapy to many, many women in order to save one. For example, for every 100 women over 50 being treated, 98 would get chemotherapy, with all its side effects but none of its benefit, in order to save two women.

This situation changed dramatically in 2003 when a company called Genomic Health burst on the scene with an elegant test to help decide who would benefit from chemotherapy. They examined DNA from thousands of breast cancer samples from women whose ultimate response (relapse or no relapse) to tamoxifen was known. They found 21 genes that accurately predicted whether a woman with hormone-positive breast cancer taking anti-estrogen therapy would relapse over the next 10 years. The result is OncoType DX, a gene expression profiling test that has now allowed many women to forgo chemotherapy with confidence.

Agendia is another biotech company whose gene profiling test was approved by the FDA this year. Called MammaPrint, it uses a 70-gene profile and has been shown to be as accurate as the Oncotype DX test in predicting breast cancer relapse.

There are differences between the two tests. Oncotype DX requires the breast cancer be lymph node-negative, early stage, and hormone receptor-positive. It can use preserved breast cancer specimens, so even if the cancer was removed years ago, the test can still be done on that tissue sample (pathologists always save tissue specimens). The MammaPrint test requires women to be early stage and lymph node-negative but does not require them to be hormone receptor-positive. However, it does require a fresh tissue sample taken at the time of surgery.

Surprisingly, many oncologists still choose not to discuss these exciting new tests with their patients.

TUMOR MARKERS
A blood test that accurately tracks metastatic cancer activity is a holy grail of sorts in the breast cancer diagnostic world. Armed with the results of this test, one can monitor the effectiveness of the current treatment regimen more quickly. Such a test, called a tumor marker, certainly has advantages over CT, MRI, and PET scans in that it can be done more frequently and without exposure to radiation.

For many years, the only choices were blood tests for CA 15.3 or CA 27.29. Unfortunately, these tumor markers were useful only for some women.

Recently, a new blood test has become available that looks for cancer cells, called circulating tumor cells, in the bloodstream. This test, called Cell Search, uses monoclonal antibodies to find as few as one cancer cell per billion normal cells in a small sample of blood.22 The FDA has approved this test only for women with metastatic breast cancer. It is available from Quest Diagnostics and many other laboratories.

Women with metastatic HER2-positive breast cancer now also have a more accurate tumor marker. Monitoring the HER-2 ECD blood test over time has proved very useful in this regard as noted by several research papers presented at the San Antonio Breast Cancer Symposium (SABCS) and the American Society for Clinical Oncology annual conference (ASCO).23,24 This FDA approved test may be obtained through Specialty Laboratories.

CELEBREX FOR METASTATIC BREAST CANCER
Last year, a group of French researchers published the results of a well-designed study looking at a new drug combination for treating breast cancer.25 They used Celebrex, a COX-2 inhibiting anti-inflammatory medication, and Aromasin, an anti-estrogen drug. This combination was prescribed as the first-line treatment for metastatic breast cancer and was compared to using Aromasin alone. The Celebrex plus Aromasin group had 75% more women whose cancer went into complete or partial remission than did those who took Aromasin alone.

Interestingly, women who took Celebrex plus Aromasin had significantly less pain, joint aches, fatigue, and insomnia. But more of these women experienced edema (about 8% versus 2% in the Aromasin alone group) and hypersensitivity reactions. In fact, anyone who is allergic to Sulfa should not take Celebrex, but should take another COX-2 inhibiting anti-inflammatory agent instead.

Although this study was done with Aromasin, other aromatase-inhibiting anti-estrogens such as Femara and Arimidex may very well work with Celebrex in the same way.

ER-NEGATIVE BREAST CANCER MAY RESPOND TO ANTI-ESTROGEN THERAPY AFTER ALL
At the December San Antonio Breast Cancer Symposium, much excitement surrounded a multinational study of the effect of aromatase inhibitors on estrogen receptor-negative breast cancer.26 In short, they tested the truism that estrogen receptor-negative cancers do not respond to anti-estrogen therapy.

This elegant study gathered the initial breast cancer samples of 116 women and noted their estrogen receptor status. Some had their cancers progress and, despite being estrogen-negative, were treated with aromatase-inhibiting anti-estrogens. It turned out that a notable 18% of these women had their cancer shrink when they took either Femara or Arimidex.

These results may mean that currently accepted methods do not always detect estrogen receptor-positivity accurately enough. In fact, recent research shows that looking for estrogen-related genes is a much more accurate way of determining estrogen receptor status than the current standard that relies on estrogen receptor dyes.27

The bottom line: when a post-menopausal estrogen receptor-negative cancer is resistant to standard treatment, it makes sense to consider trying Femara or Arimidex.

HER-2 POSITIVE METASTATIC BREAST CANCER
A recent flurry of studies have shown that women whose cancers grew while on Herceptin but continued the Herceptin treatment anyway, lived up to twice as long as those who did not.28,29,30,31

CURRENT HER-2 TESTING PROTOCOLS MAY BE INADEQUATE
A well-respected breast cancer research group called the National Surgical Adjuvant Breast and Bowel Project caused a stir at the ASCO meeting this year. They showed that the IHC and FISH protocols currently used for determining HER-2 status do not predict which women will respond to Herceptin.32 In fact, women who were IHC 2+ or less, or who were FISH-negative but received Herceptin anyway, had a 50% to 80% lower breast cancer recurrence rate than those who did not receive it.

Of course, the top researchers in the breast cancer treatment world, including the authors of this study, hastened to say that this is a preliminary study and oncologists should not be giving Herceptin to women unless they are FISH-positive or IHC 3+ positive for HER-2. While this may be sound public health policy, in an individual case that is resistant to standard treatment, it makes sense to consider trying Herceptin if it has not been tried yet.

In a related study, Italian researchers gave Herceptin to women whose cancers were HER-2 negative according to the standard protocol but were found to have the HER-2 protein in their blood (according to the serum HER ECD blood test).33 These women had more cancer shrinkage when given Herceptin than those who did not receive Herceptin.

HELP FOR “CHEMOBRAIN”
Provigil improved memory and attention in a randomized, controlled trial of women who had chemotherapy for their breast cancer. Of note, scientists from Cephalon, the pharmaceutical company that manufactures Provigil, participated in this study.34

ON THE HORIZON
I am optimistic about the continued advancement of cancer vaccines. The underlying science has been more difficult to conquer than many had envisioned. Nevertheless, the latest round of vaccines in clinical trials has shown some promise.

Vaccines for HER-2 Positive Breast Cancer
Every year sees more anti-HER-2 vaccines introduced into clinical trials. Currently, there are at least five such vaccines being tested. A particularly promising one, E75, was given to women who were at high risk for cancer relapse after receiving the standard treatment.35 There were about 60% fewer relapses at two years compared with those who did not receive E75. A Phase III trial is currently in the planning stage.

Vaccines for Metastatic Breast Cancer (HER-2 Positive and Negative)
The National Cancer Institute presented its latest data on PANVAC at the ASCO Breast Cancer Symposium. PANVAC is a fascinating vaccine that uses a virus to deliver potent immune-activating substances directly to the cancer site. It is hoped that PANVAC will mobilize the immune system to seek out and destroy every breast cancer cell in a woman’s body. While it showed some activity when used as a single agent, the recent NCI study using it in combination with the chemotherapy agent Taxotere showed promising prolonged partial remissions in the two patients who have tried it so far.37

Crying for Better Breast Cancer Screening
The most paradigm-shifting research presented at the ASCO Breast Cancer Symposium was a small study that analyzed the tears of women with breast lumps using a special machine called a mass spectrometer.38 They were able to tell who had breast cancer and who did not based on the results of a protein “fingerprint” of the tears. If these results are corroborated in further research, women may eventually be able to say goodbye to their annual mammogram.

Antiviral Therapy for Metstatic Breast Cancer
In recent years, there is accumulating evidence of a strong link between the human mammary tumor virus and the occurrence of breast cancer. Researchers at the National Cancer Institute are testing this hypothesis. They showed that nelfinavir (Viracept), a protease-inhibiting antiviral drug commonly prescribed for HIV, caused breast cancer cells to die in laboratory conditions.39 I hope it will not be long before a human clinical trial is done to answer this important question more conclusively.

Gwendolyn Stritter, MD, is a clinical advocate for those with difficult or life-threatening health problems. Her practice is focused especially on those with breast cancer. She is a member of the American Society of Breast Disease, the Society for Integrative Oncology, the American Society of Clinical Oncology, and the American Pain Society. Dr. Stritter would like to thank Michael McCulloch and Autumn Stanley for their editorial assistance. She would also like to thank Carl Stritter and Ann Baldwin for reviewing the manuscript. Visit her online at www.strittermed.org.

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