PrimeCuts: Week of August 24th

August 24, 2009

huracan_bill_sateliteJon-Emile Kenny

Faculty Reviewed

Roughly 40,000 women die each year in the United States from breast cancer, and nearly 200,000 will be newly diagnosed; we have all been affected by this disease, and this week’s PrimeCuts looks at the latest in the treatment, diagnosis and molecular pathophysiology of this common malignancy.

Four years ago, the BIG 1-98 study compared, tamoxifen monotherapy and aromatase inhibitor monotherapy (letrozole) among postmenopausal women with receptor-positive breast cancer. This early study revealed that aromatase inhibitor given alone, as compared with tamoxifen given alone, reduced the risk of recurrent disease, especially at distant sites. From that time, aromatase inhibitors alone became the staandard of care in this select group. In the most recent issue of the New England Journal of Medicine, the authors of BIG 1-98 published their remaining data: aromatase monotherapy compared to sequential treatment regimens (i.e. tamoxifen followed by an aromatase inhibitor and an aromatase inhibitor followed by tamoxifen). Using a randomized, double-blinded study with intention-to-treat analysis, the authors concluded that sequential treatment with letrozole and tamoxifen, as compared with letrozole alone, did not improve disease-free survival. Additionally, they showed that the difference in overall survival with letrozole monotherapy and tamoxifen monotherapy was not statistically significant. This is significant because there are many who cannot tolerate aromatase inhibitors due to side effect. This study enables the clinician to safely switch post-menopausal women on aromatase inhibitors (but with side effects), to tamoxifen.

What about those resistant to aromatase inhibitors? A group published data in the current issue of the Journal of the American Medical Association looking at therapy for postmenopausal women with advanced, aromatase inhibitor-resistant, hormone receptor-positive breast cancer. Notably, it was previously shown that prolonged estrogen deprivation (e.g. post-menopausal or pharmacological) provoked cells to apoptose when exposed to estradiol. Similarly, the unexpected decrease in breast cancer incidence observed in women receiving equine estrogens in the Women’s Health Initiative Trial stimulated interest in the possibilities of low-dose estrogen therapy for breast cancer. The authors utilized a randomized, double-blind methodology and compared 6 mg of estradiol to 30 mg in aromatase inhibitor-resistant breast cancer. While there was no ‘control group’ in the study, the clinical benefit rates of both groups were equal and similar to other endocrine therapies in patients with advanced disease. Equally interesting was the observed potential for resensitization to anti-estrogen therapy by estradiol treatment – the mechanism of which is currently unknown.

What about progesterone antagonists?  An experimental rat model of breast cancer has shown that a progesterone antagonist, in addition to the anti-estrogen tamoxifen, resulted in high remission rate – comparable to oophorectomy. A research group from Japan demonstrated that combination estrogen and progesterone antagonists up-regulated progesterone receptors on tumor cells and lowered systemic progesterone levels despite a small increase in LH secretion. Taken together these findings suggest that the high anti-tumor effect of the combination therapy may be related not simply to the interaction of anti-hormones and receptors, but also to the change in progesterone receptor density and to a decrease in progesterone production. Their data, published in the most recent edition of The Journal of Steroid Biochemistry and Molecular Biology, suggest a role for combination treatment in breast cancer.

Her2 positive breast cancers are treated with antibodies directed against this receptor. But what is the mechanism for Her2 amplification? As noted in an excellent Grand Rounds last year given by Dr. Jose Baselga, Advances in the Therapy of HER2 Positive Breast Cancer, Her2 multiplies on the surface of breast epithelial cells and acts as an oncogene. Gene amplification is seen in many forms of human disease including congenital (e.g. Fragile X syndrome), neurological (e.g. Huntington’s Chorea) and malignant disorders. Researchers in this week’s issue of Nature have elucidated many of the eukaryotic pathways by which genome stability (i.e. prevention of gene amplification) is maintained. In the future, patients with defects in these pathways may be sought for early screening, much as the BRCA patients are today.

DNA no longer monopolizes the oncogene status. Classical cancer genetics teaches us that genes responsible for promoting cell division may obtain ‘gain of function’ mutations and become pro-cancerous. Other genes that inhibit cell growth may suffer ‘knock out’ mutations and similarly enhance a cell’s malignant potential. These are the theoretical oncogenes and tumor suppressor genes, respectively. In the last five years, however, microRNAs, single-stranded RNA molecules that play an important regulatory role in cell biology, have been characterized. They bind to target genes and alter their function. In the Journal of Biological Chemistry researchers have recently shown that MicroRNAs may also act like oncogenes. Specifically, invasive breast cancer cell lines were found to have elevated levels of miR-27b, a microRNA that inhibits ST14, a gene responsible for stopping cell division. These novel cell-regulatory molecules provide potentially new targets for invasive breast cancer.

Human breast tissue is composed of epithelial cells organized into a branching network of ducts and lobules. Describing subsets of these cells is a prerequisite for understanding the molecular pathophysiology of breast cancer. In this month’s issue of Nature Medicine, three subtypes of ductal epithelial cells were characterized in both normal and BRCA1 positive tissue. Surprisingly, the luminal progenitor subtype and not the mammary stem cell line, was found to have factor-independent (i.e. malignant) growth in BRCA1 positive lines. The mechanism of BRCA1 breast cancer has been attributed to multiple mechanisms including: DNA mismatch-repair defects, X chromosome inactivation and cell cycle control. The elucidation of a distinct cell type will facilitate tumor targets and direct current therapy. Notably, the estrogen receptor was expressed by a substantial fraction of human luminal progenitor cells and may explain the partial efficacy provided by prophylactic oophorectomy and tamoxifen chemoprophylaxis in the prevention of basal breast tumors in BRCA1 mutation.

Dr. Kenny is a third year resident in the NYU School of Medicine Internal Medicine Residency Program and a future Chief Medical Resident.   The post was reviewed by Dr. Judith Brenner, an Associate Program Director and Associate Editor of


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3. Ellis MJ, et al. Lower-Dose vs High-Dose Oral Estradiol Therapy of Hormone Receptor-Positive, Aromatase Inhibitor-Resistant Advanced Breast Cancer. JAMA 2009;302(7):774-780.

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6. Wang Y, et al. ST14 Gene is a Target for miR-27b.  Journal of Biological Chemistry 2009;284(34):23094-106.

7. Lim E, et al.  Aberrant Luminal Progenitors as the Candidate Target Population for Basal Tumor Development in BCRA1 Mutation Carriers.  Nature Medicine 2009;15:907-13.