Approved for Osteoporosis, Bazedoxifene (BZA) shows Promise, Even in Cancer of Breast Resistant to Tamoxifen

Now, there are several drugs for treatment of osteoporosis, commonly advised is a group of drugs called bisphosphonates. Commonly used bisphosphonates are alendronate, rosedronate and zolendronic acid etc..

The mode of administration may be oral or intravenous; for orally usable ones, there are specific advices like to be taken in empty stomach, patient remain without food, and in erect position for at least one hour after taking the drug etc.. Taking the drug in IV (Intravenous) route and following the instructions for oral intake may not be patient compliant too.

Bazedoxifene (BZA) from the family of drugs called SERMs (Selective Estrogen Receptor Modulators) that act in different way in different tissue expressing estrogen receptors; bone friendly (Agonist activity), but against breast (Antagonist); whereas bisphosphonates are antagonistic to all the tissue. In contrast to bisphosphonates, there is no specific instruction of oral intake of the drug.

Structural diagram of bazedoxifene. Created using ACD/ChemSketch 8.0 and Inkscape. (Photo credit: Wikipedia)

Bisphosphonates have the bad reputation of causing atypical fractures and osteonecrosis of jaw bones.

That is why, bezedoxifene may be considered as a safer alternative to the bisphosphonates. BZA has also been paired with conjugated estrogen (CE) in menopausal therapy called TSEC (Tissue Specific Estrogen Complex) for the prevention of osteoporosis and treatment of menopausal symptoms.

It was recently approved in the European Union for the treatment of osteoporosis in post-menopausal women at increased risk of fracture. The potential of this drug to treat the condition has been well documented in SMART (Estrogens, Menopause, And Response to Therapy) trial.

The benefits from tamoxifen and aromatase inhibitors like letrozole in breast caner treatment after surgery and chemotherapy in estrogen positive (ER+) tumours are invaluable in post-menopausal patients. Recently, researchers started recommending tamoxifen for 10 years instead of 5 years for this reason.
In a substantial number of patients, eventually, after initial response to tamoxifen treatment, cancers do recur. Treatment with tamoxifen, which is a SERM that works on tissue expressing estrogen receptor all over the body, makes patient prone for osteoporosis in absence of estrogen in bone, in a situation, where as such, there is lack of the hormone in post-menopausal state.
Now, it has been seen that bazedoxifene, like tamoxifen, although belongs to class of (SERMs); but unlike tamoxifen, has some of the properties of a newer group of drugs, known as selective estrogen receptor degraders, or SERDs, which can target the estrogen receptor for destruction in selective tissue.
These drugs are distinguished by their ability to behave like estrogen in some tissues, while significantly blocking estrogen action in other tissues.
It even works in case of breast cancers that has become resistant to treatment of tamoxifen and aromatase inhibitors because of this property.
So, it remains to be seen, if the drug can come out as a winner, to be recommended for treatment of breast cancer too; in which case, it will be a drug addressing two issues at one time i.e. breast cancer treatment and prevention of osteoporosis in those patients.

Related articles

• Osteoporosis drug stops growth of breast cancer cells, even in resistant tumors
• Osteoporosis drug stops growth of breast cancer cells, even in resistant tumors

Risk Factors for Breast Cancer

Breast cancer is a commonly diagnosed cancer in women after non-melanoma skin cancer, and it is the second leading cause of cancer deaths after lung cancer.

heredity and cancer, breast cancer, inherited factors vs. other factors (Photo credit: Wikipedia)

Family History of Breast Cancer

It has been seen in studies in adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first-degree relative (FDR) or a second-degree relative with breast cancer.

Risk increases with the number of affected relatives, age at diagnosis, and the number of affected male relatives

Genetically predisposed/Inheritance

Autosomal dominant inheritance of breast cancer is characterized by transmission of cancer predisposition from generation to generation, through either the mother’s or the father’s side of the family, with the following characteristics:

• Multiple cancers within a family.
• Cancers typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk).
• Two or more primary cancers in a single individual. These could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancer of different types (e.g., breast cancer and ovarian cancer in the same individual).
• Cases of male breast cancer.

Other Risk Factors for Breast Cancer include age, reproductive and menstrual history, hormone therapy, radiation exposure, mammographic breast density, alcohol intake, physical activity, anthropometric variables, and a history of benign breast disease

• Age

·         Risk of breast cancer increases with age, with most breast cancers occurring after age 50 years. In women with a genetic susceptibility, breast cancer, tends to occur at an earlier age than in sporadic cases.

• Use of Oral Contraceptives

·         Oral contraceptives use are not entirely consistent, however, use of OCs formulated before 1975 was associated with an increased risk of breast cancer.

·         Oral contraceptives (OCs) may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect.

• Hormone replacement therapy (HRT)

·         Data exist from both observational and randomized clinical trials regarding the association between postmenopausal HRT and breast cancer.

·         Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.

·         Local use of hormone cream is safer than oral preparations.

• Age at Menarche, Parity and Menopause.

·         In general, breast cancer risk increases with early menarche, late menopause; and is reduced by early first full-term pregnancy.

·         In contrast to ER-positive breast cancers, parity has been positively associated with triple-negative disease, with no association with ages at menarche and menopause.

• Radiation exposure

·         Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure.

·         The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear.

·         Frequent mammograms are also not recommended.

• Alcohol intake

·         The risk of breast cancer increases by approximately 10% for each 10 g of daily alcohol intake (approximately one drink or less) in the general population. Prior studies of BRCA1/BRCA2 mutation carriers have found no increased risk associated with alcohol consumption.

• Physical activity and anthropometry

·         Weight gain and being overweight are commonly recognized risk factors for breast cancer. In general, overweight women are most commonly observed to be at increased risk of postmenopausal breast cancer and at reduced risk of premenopausal breast cancer. Sedentary lifestyle may also be a risk factor. One study suggested a reduced risk of cancer associated with exercise among BRCA1 and BRCA2 mutation carriers.

• Benign breast disease (BBD) and mammographic density

·         Benign breast disease (BBD) is a risk factor for breast cancer, independent of the effects of other major risk factors for breast cancer (age, age at menarche, age at first live birth, and family history of breast cancer). There may also be an association between BBD and family history of breast cancer.

·         An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram, and breast density is likely to have a genetic component in its etiology.

With a normal active lifestyle, balanced diet; and breast self examination can beat the dreaded cancer to a larger extent.

Tamoxifen is being thought as a Preventive Medication for Breast Cancer in High Risk Women

English: Most common cancers in the United States 2008. See Epidemiology of cancer (Photo credit: Wikipedia)

Each year almost 50,000 women are being diagnosed with breast cancer. Out of which, around 2,400 have inherited defective breast cancer genes, while a further 5,000-7,000 are affected by genes not yet identified.

Women with faulty genes such as BRCA1, BRCA2 and TP53 are among those at high risk for developing breast cancer, accounting for at least 4 per cent of all women.

The risk of breast cancer in the general population is one in eight – but this rises to one in three for women at high risk and one in four for those at moderate risk.

Having a family history of breast or ovarian cancer can significantly increase the risk of developing breast cancer and at a younger age, although most women with a relative with breast cancer are not at a substantially increased risk themselves.
National Institute of Health and Clinical Excellence (NICE) says under 1% of women over 30 fall into the high-risk category. NICE says not enough is being done to help healthy but high-risk women, who include women with a sister and a mother or aunt diagnosed with breast cancer before the age of 50.
Tamoxifen, an estrogen receptor (ER) inhibitor, has been used to treat the illness for more than 30 years, saving the lives of hundreds of thousands at a low cost, although newer drugs are proving even more effective.
Based on research findings, experts estimate that for every 1,000 women given tamoxifen, there would be 20 fewer breast cancers.
New draft guidelines suggest the drugs tamoxifen or raloxifene (A drug for osteoporosis) could offer as much as 20 years of protection for those considered at high risk of cancer.
The new draft guidelines for England and Wales, which would update recommendations made by NICE in 2006, apply to these women and focus on areas of care where new evidence has been published, which includes using tamoxifen as a preventative treatment.
The National Institute of Health and Clinical Excellence has launched a consultation on whether tamoxifen could be given for up to five years.
The Nice proposals could also lead to more genetic testing. Women with some genetic mutations could be offered annual MRI scans from the age of 20 to 49.

Those at moderate risk could be given annual X-ray scans from 40, while others could receive annual checks after the age 50 instead of three-yearly checks with the routine NHS screening programme.

Women in England and Wales with a strong family history of breast cancer could be offered medication on the NHS to try to prevent the disease.
Both drugs are already used in other countries to prevent breast cancer, for example in the United States, where they have been approved for that purpose by the federal Food and Drug Administration.
Nice is recommending that pre-menopausal women at high risk should be offered tamoxifen unless they have a history of thromboembolic disease or endometrial cancer, and that post-menopausal women with the same medical history who are at high risk should be offered either drug, in both cases for five years.
In addition, doctors should consider prescribing tamoxifen to pre-menopausal women at moderate risk of developing breast cancer within the next 10 years, and either drug to post-menopausal women with the same risk, again in both cases for five years, Nice's guideline says.The aim is to slash the odds of developing breast cancer in the first place – just as statins are given to patients to reduce cholesterol.
If approved later this year, the draft guidelines would be the first of their kind in the UK.


Related articles

• 'Historic' breast cancer drug move
• 500,000 women to be offered breast cancer drugs

How to Screen/Image Dense breasts for Detection of Cancer

It is difficult to get image of breast abnormality or tumour in case of dense breasts in mammography, where a cancer may not be detected at an early stage; consequently giving rise to possibility of cancer spreading to distant places.
It is mandatory in US to inform the patient of the density of her breast tissue. Now, a new legislation is going to be framed by which it will be essential to inform the patient that the radiation dose from mammography may cause new cancer.
The laws owe their existence mostly to Nancy M. Cappello, 59, of Woodbury, Conn. She was not told that she had dense breast tissue until after doctors found an advanced cancer that mammograms had missed. She took her story to legislators, and in 2009, Connecticut became the first state to require that women be told if they have dense breasts and that insurance companies cover ultrasound scans for those women.
Ms. Cappello, the woman who started the movement to inform patients, began having yearly mammograms at age 40. In 2004, when she was 51, her doctor felt a lump in her breast — only six weeks after a mammogram had looked normal. Even after the lump was detected, mammography still could not find it. Only then was Ms. Cappello told that she had dense breast tissue. The cancer had already spread to 13 lymph nodes. She needed a mastectomy, chemotherapy, radiation and hormone treatment.
Breast consists of glandular, fibrous and fatty tissue apart from other tissue in small proportions. “Dense” breasts have a relatively high proportion of glandular or connective tissue, which blocks X-rays. Non-dense breasts have more fat, which X-rays penetrate easily.

Left~Dense Breast, Right~Non-dense with Abnormality

Over all, about 40 percent of women who have mammograms have dense breast tissue. Younger women are more likely to have dense tissue, but as many as 25 percent of older women do, too. Density cannot be judged by touch; it shows up only on mammograms.
The National Cancer Institute calls dense breasts “a strong risk factor for developing breast cancer.” Various studies have estimated that compared with other women, those with dense breasts are two to six times as likely to develop breast cancer. The reason is not known. But dense breasts have more milk ducts and lobes, where most cancers form, so some researchers think the added risk may come from having more of that tissue.
On mammograms, dense breasts look white, and so does cancer, so the tissue can hide tumors. Fatty breasts show up mostly black, so tumors stand out.
Studies have found that when women with dense breasts were given mammograms and then ultrasounds, the ultrasound found tumors that the mammograms missed — but also produced many false positives that led to biopsies.
Studies of women with dense breasts that were published in June in the journal Radiology and in April in The Journal of the American Medical Association found that for every 1,000 women screened, adding ultrasound found three to five cancers that mammograms missed. But in one study, 63 biopsies or other invasive procedures were performed to find three tumors.
M.R.I. exams can also find tumors that mammograms miss, but they produce even more false positives.
Despite its shortcomings, mammography does find some tumors in women with dense breasts — including some that ultrasound misses — so doctors emphasize that these women should not skip mammograms.
So, it is advisable to have ultrasound of breast, if mammogram labels the breast to be dense. Recently, it has been recommended to have ultrasound in females below 40 years of age. As a supportive diagnostic tool in case of families of breast cancer, where there is still suspicion MRI can be performed. All the imaging results may be studied together to arrive at a conclusion.
The ladies subjected to mammography should always read their report for the possibility of having dense breasts reported according to the American College of Radiologists (ACR).