The incidence of breast cancer is rising throughout the world.  Breast cancer is slowly becoming more prevalent in countries which previously had low rates of cancer as well as becoming a leading cause of cancer death in some countries.  Fortunately, a large number of these tumors are estrogen receptor (ER) positive and respond to anti-hormonal adjuvant therapy which until recently has been 5 years of tamoxifen treatment. 

Unfortunately, a significant number of patients develop recurrent cancers and the recurrent tumors are resistant to tamoxifen treatment.  In addition,  because of tamoxifen’s selective estrogenic actions, there have been reports of venous thrombosis, endometrial cancer, and strokes in patients receiving tamoxifen therapy.  Thus,  there are other novel therapies such as aromatase inhibitors that block estrogen production in postmenopausal women or fulvestrant that destroys the estrogen receptor. 

This paper will summarize the therapeutic options for anti-hormonal therapy, the role of anti-hormonal agents in advanced breast cancer, and adjuvant therapy and the current status of chemoprevention with selective ER modulators.
Breast Cancer 14:113-122, 2007.

Key words: Tamoxifen, Aromatase inhibitors, Fulvestrant, Estrogen receptor

Introduction
There are approximately 1,000,000 new cases of breast cancer in the world each year¹).  Unfortunately,  as we increase our understanding of the biologic behavior of these tumors,  the incidence of breast cancer continues to rise throughout the world.

There are currently over 2 million breast cancer survivors in the United States.  This year, there will be an estimated 212,920 new cases of invasive breast cancer with the rate of invasive breast cancer increasing by 0.3%  per year since 1987²). According to the surveillance, epidemiology,  and end results (SEER)  from the 1998-2002 National Institutes of Health databases, there was an incidence of 501.8 cases of breast cancer per 100,000 women in the United States during this time period.  The mortality rate was 103.8 per 100,000 women²).  On a stage by stage basis, 55% of women had stage 0-1 breast cancer.  The next largest group had stage 2 breast cancer and constituted 30%  of the patients.  Stage 3,  4,  and unstaged breast cancer each constituted 5 %  of breast cancer patients³).

In Japan,  the incidence of breast cancer is much lower than the United States.  However, the incidence has been rising steadily.  Since 1975, the incidence of breast cancer has more than doubled.

In 1975,  approximately 15/100,000 women developed breast cancer.  By the year 2000,  approximately 45/100,000 women developed breast cancer.  The majority of the women with breast cancer were 50 years of age or older⁴).  Additionally, from 1970-1999,  out of approximately 15 million women who were screened, 2,340 cases of breast cancer were detected.  In the time period between 1999-2000 alone,  there were 1,168 new cases of breast cancer out of 986,913 patients screened⁵).

In 2001,  approximately 9,654 women died of breast cancer in Japan⁶).  By the year 2020,  the Japanese Cancer Registry estimates that the annual incidence of breast cancer will be 127,000 in Japan if current trends continue⁷).

The discrepancies in breast cancer incidence and the trends in an increased incidence in Japan lead one to question the underlying cause.

Throughout history,  scientists have noted that breast cancer occurred at a higher frequency in nuns and nulliparous women.  Also,  first childbirth at a later age correlates with breast cancer risk.  In western countries, childbearing occurs at a later age.  Traditionally, Japanese women tend to have more children and start having children at a younger age.  Obesity and diets high in saturated fats such as American diets also correlate with higher rates of breast cancer.  Traditional Japanese diets are 10-25% fat, whereas U.S diets are 40- 45% fat⁸).  In the past decade, more Japanese women are having children at a later age, fewer children, and have adopted more of a “western” diet which may explain the rise in breast cancer incidence⁹).

What does this mean?  Progesterone causes maturation of the glandular breast tissue during pregnancy,  so early pregnancy can be viewed as chemoprevention.  In nulliparous women, the breast tissue is exposed to unopposed estrogen,  which causes proliferation of the gland.  Higher fat stores in the body lead to higher levels of peripheral   estrogen,  particularly   during   the   post-menopausal period.  Thus, estrogen can be viewed as promoting estrogen responsive breast cancer development.  In the United States,  this is evidenced by a rise in estrogen receptor (ER)  positive breast cancer and a decrease in ER negative breast cancers¹⁰).  Since 1990, the SEER database in the United States has been updated to include ER positive and ER negative breast cancers.  Out of 82,488 breast cancer patients from the 1992- 1998 databases,  25%  of the women had ER negative cancer and 75% of the women had ER positive cancer.  Of those patients with ER negative cancer, 21% were greater than 50 years of age, while 37% were less than 50 years of age¹¹).

In Japan, a few small studies have been undertaken at various hospitals looking at cases from the 1970’s to determine the percentage of ER positive cancer.  No recent studies have been found.

One early study demonstrated that 55%  of 456 patients had ER positive breast cancer.  The distribution was similar between pre-menopausal and post-menopausal patients¹²).  Another paper compared international studies of ER positive cancer in the 1970’s¹³).  The rate of ER positive breast cancer in a study from 1977 was 58% (1060 patients) in Japanese and 71%  in American women.  The patients were further categorized into premenopausal and postmenopausal patients. At this time, 57%  of premenopausal Japanese women had ER positive cancer and 59% of premenopausal American women studied had ER positive cancer.  The discrepancy in ER positive status was primarily between postmenopausal patients in both countries.  Postmenopausal Japanese women had 59% ER positivity, while 71% of postmenopausal American women were ER positive¹⁴).  Another study compared 260 patients from Japan with 410 patients in Western countries. The regression rate of ER positive tumors to endocrine therapy was 48% and 55%,  respectively¹⁵).  Regardless of the difference in ER positive tumors, the response to endocrine therapy was similar.

Clearly, it would be interesting to compare the current incidence of ER positive tumors between Japan and Western countries.  Since the incidence of breast cancer is rising in Japan and many Japanese women have adopted “western” lifestyles, one would hypothesize that the incidence of ER positive breast cancer has risen in Japan.

The pioneering work of Elwood Jensen¹⁶)  identified the ER as the signal transduction pathway that controls the growth of the majority of breast cancers.  The ER subsequently became the therapeutic target for the development of antiestrogenic drugs¹⁷).  Thus, antihormonal therapy plays an important role in the therapeutic armamentarium for high risk patients and those patients with a diagnosis of breast cancer.  Several established options to treat ER positive breast cancer are now available since the introduction of tamoxifen to Japan more than 20 years ago.