Breast Cancer

Multi-targeted TKI inhibitors are gaining traction in the treatment of advanced breast cancer, although results from four different trials do show varying degrees of efficacy.

A 30-year study of nearly 20,000 Danish women made a defensible connection between obesity and poor prognosis after breast cancer diagnosis and treatment.

The targeted combination of lapatinib (Tykerb) plus trastuzumab (Herceptin) led to a median overall survival of 14 months in women with refractory metastatic breast cancer.

The Four Corners Breast Cancer Study is a population-based case-control study of women living in the southwestern states-Arizona, New Mexico, Colorado, and Utah.

The standard for delivering the best quality of care to breast cancer patients calls for surgeons to consult with other specialists and to provide resources and education to help patients decide their course of treatment. That doesn't mean they do it.

Pharmacologic strategies targeting the DNA of tumor cells have been in use for much of the past century for many different cancer types. Radiation has also been a long-employed strategy to cause DNA damage and subsequent tumor cell death. However, the class of agents designed to inhibit the enzyme poly-(ADP-ribose) polymerase (PARP) have taken this a step further-these agents do not damage DNA themselves, but rather, inhibit the repair of DNA via inhibition of the base excision single-strand repair pathway. PARP inhibitors have been shown preclinically and clinically to enhance the affects of chemotherapies known to damage DNA or interefere with DNA replication. However, the most exciting use of PARP inhibitors may be in exploiting the concept of synthetic lethality. In this setting, the concept is based on two factors: (1) BRCA1/2-positive malignancies cannot use one of the major pathways to repair double-strand DNA breaks (ie, homologous recombination), and (2) making the base excision repair pathway nonfunctional via inhibition of PARP leads to tumor cell death, as unrepaired single-strand breaks are converted into double-strand breaks.

In this issue of ONCOLOGY, Comen and Robson provide a timely overview of poly(ADP-ribose) polymerase (PARP) inhibitors and their potential for the treatment of breast cancer. The authors highlight the recent demonstration of synthetic lethality between PARP inhibition and loss of either of the breast cancer susceptibility genes, BRCA1 and BRCA2, as well as the development of PARP inhibitors that are suitable for clinical therapy. However, many questions pertaining to both the basic biology of PARP inhibition and the potential clinical implications of PARP inhibitors still need to be addressed. In the following commentary, we highlight some of these remaining challenges.

As knowledge increases about the processes underlying cancer, it is becoming feasible to design “targeted therapies” directed toward specific pathways that are critical to the genesis or maintenance of the malignant phenotype. Poly(ADP-ribose) polymerase (PARP) inhibitors are an example of this new framework. DNA damage repair is a complex and multifaceted process that is critical to cell survival. Members of the PARP family are central to specific DNA damage repair pathways, particularly the base excision repair (BER) pathway. PARP inhibition, with subsequent impairment of the BER mechanism, may enhance the cytotoxicity of agents that generate single-strand breaks in DNA, such as radiation and certain chemotherapy drugs. In addition, PARP inhibitors may induce death through “synthetic lethality” if the DNA repair mechanisms that rescue BER-deficient cells are themselves impaired. This mechanism is thought to underlie the impressive results of PARP inhibition in BRCA-associated breast and ovarian cancer, and may also account for the reported benefit of this approach in “triple-negative” breast cancer. This review will examine the current understanding of PARP inhibition as a treatment for breast cancer, ongoing clinical trials, and future directions for this new approach.

A U.S. Preventive Services Task Force recommendation that routine breast cancer screening should begin at age 50, and take place every two years, did not sit well with the breast cancer community. The new recommendations will result in “many needless deaths,” stated the Society of Breast Imaging and the American College of Radiology.

Over 40 million men and women in the United States have osteoporosis and low bone mineral density (BMD), placing them at risk for adverse skeletal events such as fractures and their sequelae. There are over 12 million cancer survivors in this country. Of these, 22% were diagnosed with breast cancer and 17% with prostate cancer.[1,2] Because cancer therapies can adversely influence bone health, these survivors are at particular risk for skeletal complications. Cancer therapies associated with bone loss include hormone deprivation therapies such as aromatase inhibitors, ablative surgical procedures that induce hypogonadal states, and premature menopause induced by chemotherapy.[3,4]

Many women continue to experience pain and sensory disturbance up to three years after breast cancer treatment, according to Danish researchers, who found that younger women in particular reported persistent pain. They called for further strategies for improving pain management after breast surgery.

This article will review and summarize the current data regarding the influence of the major cytochrome P450 2D6 (CYP2D6) genotypes and CYP2D6 inhibitors on tamoxifen metabolism and clinical efficacy. We will discuss the clinical relevance and limitations of this data and how to best incorporate our current understanding of CYP2D6 genotyping into our clinical practice and discussions with patients.

In the post–Human Genome Project era, “personalized medicine” has become a buzzword. Health-care professionals increasingly have access to gene sequence data, with the promise that this information will improve the health of the individual. In the area of breast oncology, the study of genetic markers associated with clinical outcome has been a relative success story.

The promise of pharmacogenetics is personalization of therapy for individuals through refinement of the risk/benefit profile of pharmaceuticals based on inherited gene mutations. Classic examples of the impact of pharmacogenetics in clinical practice include variants in dihydropyrimidine dehydrogenase and treatment with fluorouracil.

A 56-year-old woman was referred to our institution for a left nephroureterectomy after the diagnoses of a nonfunctioning left kidney and noninvasive papillary urothelial carcinoma of the distal left ureter (Ta grade 1). Following the procedure, surveillance cystoscopy and computed tomography (CT) scan of the abdomen and pelvis demonstrated a large bladder tumor with pan-urothelial extension.

The targeted combination of lapatinib (Tykerb) plus trastuzumab (Herceptin) led to a median overall survival of 14 months in women with refractory metastatic breast cancer, according to an updated analysis of the phase III EGF104900 trial. A bonus: The majority of toxicities were low-grade.

Despite a better dose loading schedule and compelling preclinical data, the combination of fulvestrant and anastrozole did not demonstrate any advantage in first relapse of hormone receptor-positive breast cancer, according to first results from the FACT trial.

Researchers in Taiwan and China found that alternating mammography and ultrasound led to a higher cancer detection rate in women aged 40-49. Meanwhile in the UK, a group from West Midlands Research Collaborative have made a case for starting screening at age 40 in certain ethnic groups. Finally, German investigators assessed the value of semi-annual ultrasound exams in high-risk women.

The RIBBON-2 trial met its primary endpoint to prolong progression-free survival, making the bevacizumab-chemotherapy combination a new treatment option, said principal investigator Adam Brufsky, MD. The trial continued the evaluation of bevacizumab plus chemotherapy to treat metastatic breast cancer after previous treatment failures.

Along with many other health issues, obese breast cancer patients face a particularly grim prognosis, with an amplified risk of recurrence and an increased risk of dying of the disease, according to results from a long-term, large-scale study in a Danish population. The researchers also noted that a larger body habitus negatively impacted treatment results.

Denosumab prevented more events, was better tolerated, and was more convenient for breast cancer patients with skeletal metastasis, according to results from a randomized double-blind trial that matched the RANK ligand inhibitor against zoledronic acid.

Exemestane alone and exemestane following tamoxifen, are equally appropriate treatment options, according to results from TEAM, the first trial prospectively powered to test the superiority of five years of aromatase inhibitors compared with a specific sequential strategy in postmenopausal women with endocrine-sensitive breast cancer.

Ultrasound is an effective way to monitor lymph node recurrence after breast cancer surgery, South Korean researchers reported. Regional lymph node recurrence affects just 2% to 16% of patients with any stage of breast cancer, but is difficult to manage and associated with poor prognosis.

The skeletal health of pre-menopausal women with estrogen receptor-negative breast cancer took a beating after six cycles of doxorubicin (Doxil)/cyclophosphamide (A/C) chemotherapy.

In their recent commentary (Oncology 23:639-641, 2009), Labriola and colleagues reviewed the data on “natural” hormone replacement and breast cancer risk. The “natural” agents were bioidentical and phytoestrogen supplements to manage vasomotor symptoms in breast cancer patients.