Breast Cancer

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < -2.5) and considered on an individual basis for those with osteopenia (T score < -1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.

This month ONCOLOGY presents a special desk reference on the treatment and management of women with breast cancer, including discussion about adjuvant treatment of early disease and first-line cytotoxic chemotherapy for metastatic breast cancer.

Over the past 20 years we have witnessed the emergence of a new generation of aromatase inhibitors as valuable antiestrogens in the management of both advanced and early-stage breast cancer. In addition, the list of cytotoxic chemotherapeutic agents useful in the control of breast cancer has grown considerably. The emergence of anthracyclines was a major chemotherapeutic step forward in the 1980s, and the taxanes have clearly been the agents with the greatest impact on breast cancer treatment over the past decade. The end of the past 2 decades has been characterized by a greater understanding of the molecular biology of breast cancer, rational drug design, and the development of agents that disrupt specific cellular targets and pathways. The development of better prognostic and predictive assays that employ a panel of genes involved in the malignant and metastatic phenotype promises to allow clinicians to better select patients who could forgo adjuvant chemotherapy. Finally, adjunctive and supportive therapy of breast cancer has evolved substantially over the past 20 years. This review will highlight some of the landmark accomplishments during this time, and offer a glimpse at where we might be 20 years from now.

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past few years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate therapy but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. The condition involves exposed bone of the maxilla or mandible. Although it is often associated with a recent dental surgical procedure, spontaneous ONJ can also occur. Patients commonly present with symptoms. Through case reporting and clinical experience, there is a suggestion that the incidence of ONJ in patients with cancer receiving intravenous bisphosphonates ranges between 1% and 10%. Management of ONJ focuses on maximizing oral health, conservative actions with mouth rinses, antibiotics, and avoidance of unnecessary invasive dental procedures. The currently available data on ONJ are reviewed here.

Over the past 20 years we have witnessed the emergence of a new generation of aromatase inhibitors as valuable antiestrogens in the management of both advanced and early-stage breast cancer. In addition, the list of cytotoxic chemotherapeutic agents useful in the control of breast cancer has grown considerably. The emergence of anthracyclines was a major chemotherapeutic step forward in the 1980s, and the taxanes have clearly been the agents with the greatest impact on breast cancer treatment over the past decade. The end of the past 2 decades has been characterized by a greater understanding of the molecular biology of breast cancer, rational drug design, and the development of agents that disrupt specific cellular targets and pathways. The development of better prognostic and predictive assays that employ a panel of genes involved in the malignant and metastatic phenotype promises to allow clinicians to better select patients who could forgo adjuvant chemotherapy. Finally, adjunctive and supportive therapy of breast cancer has evolved substantially over the past 20 years. This review will highlight some of the landmark accomplishments during this time, and offer a glimpse at where we might be 20 years from now.

Studies have suggested that women with low incomes residing in metropolitan areas might be less likely to be screened for breast cancer than more affluent women residing in the same areas.[1,2] However, few studies have examined the associations between breast cancer screening and both individual and area-based measures of socioeconomic status among women in metropolitan areas.[3,4] To examine these associations, the Centers for Disease Control (CDC) analyzed the percentage of women who had a mammogram by using individual data (ie, household income and education level) from the 2000 and 2002 Behavioral Risk Factor Surveillance System (BRFSS) surveys and area-based data (ie, percentages classified as living in poverty [annual family income below the federally defined poverty line] or at a low education level [less than a high school education]) from the 2000 US Census.

The patient presented to her primary care physician 3 months prior with an inverted left nipple and a palpable lump that was highly suggestive of neoplasm on mammogram. An ultrasound-guided core biopsy revealed an infiltrating solid-type ductal carcinoma in situ. The estimated size of the mass was approximately 1 cm. She had no symptoms suggestive of metastatic disease.

Genentech Seeks Expanded Use of Avastin in Breast Cancer

The monoclonal antibody denosumab (AMG 162) attenuates bone resorption in patients with breast cancer who have bone metastases as effectively as bisphosphonates, according to interim results of a trial reported at the 2006 ASCO meeting (abstract 512).

Investigators have begun enrolling women with early-stage breast cancer in the Trial Assigning Individualized Options for Treatment (Rx), commonly referred to as TAILORx, a long-term study designed to determine whether oncologists can use the Oncotype DX (Genomic Health, Inc.) recurrence score to assign women to the most appropriate and effective adjuvant treatments.

Peri- and premenopausal women may be more at risk for cognitive impairment than postmenopausal women as a result of adjuvant chemotherapy for breast cancer, according to preliminary data presented at the American Psychosocial Oncology Society (APOS) Third Annual Conference (abstract P3-5).

New data from a 5-year update of the bone subprotocol of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial confirm that women with a normal bone mineral density (BMD) at the outset of treatment may be able to undergo a 5-year course of therapy with anastrozole (Arimidex) without the risk of developing osteoporosis.

GlaxoSmithKline (GSK) announced results from a large, randomized, pivotal phase III study of its investigational small-molecule dual kinase inhibitor lapatinib ditosylate (Tykerb). In this study, the combination of lapatinib and capecitabine (Xeloda) vs capecitabine alone nearly doubled time to progression (36.9 weeks in the combination arm vs 19.7 weeks with capecitabine alone, P = .00032) in women with refractory advanced or metastatic HER2 (ErbB2)-positive breast cancer whose disease had progressed following treatment with trastuzumab (Herceptin) and other cancer therapies.

Young, black breast cancer patients are much more likely than young white patients to have tumors that lack receptors for estrogen, progesterone, and HER2, according to a new, population-based study in about 500 women. This means that many breast cancer patients, including almost half of young black patients, "have tumors for which there is no targeted therapy," said lead author Mary Jo Lund, PhD, assistant professor of epidemiology, hematology, and oncology, Rollins School of Public Health and Winship Cancer Institute, Emory University, Atlanta.

Lapatinib (Tykerb), an oral small-molecule reversible dual inhibitor of HER1 (EGFR) and HER2 tyrosine kinases, is emerging as a promising option for HER2-positive breast cancer patients, investigators of phase II and III trials reported at the 42nd Annual Meeting of the American Society of Clinical Oncology (ASCO). Clinical evidence suggests that lapatinib, unlike trastuzumab (Herceptin), can cross the blood-brain barrier to treat brain metastases, which develop in about one-third of HER2-positive breast cancer patients.

Vitamin D appears to lower the risk of breast cancer, but far greater amounts are needed than most women normally take in, according to two studies presented at the 97th Annual Meeting of the American Association for Cancer Research.

Treatment of metastatic breast cancer is "a book with many chapters, ie, with many opportunities for meaningful intervention, as opposed to pancreatic cancer, for example," Andrew Seidman, MD, said in his discussion of metastatic breast cancer at the Second Annual Advances in Oncology meeting, sponsored by the journal ONCOLOGY.

Abandoning the tamoxifen market to its generic competitors, AstraZeneca will cease commercial manufacturing of Nolvadex by the end of June. "Once commercial supplies are exhausted, your patients will no longer be able to obtain brand name Nolvadex tablets," Kenneth A. Kern, MD, the company's director of clinical research, wrote health care professionals in a letter released by the US Food and Drug Administration.

According to a new study, women who gain weight in adulthood face a higher lifetime risk of all types of breast cancer even if they do not take hormone replacement therapy after menopause. To be published in the July 1, 2006, issue of CANCER, the study reveals that the greater the weight gain as an adult, the greater the risk for all histologic types, tumor stages, and grades of breast cancer, particularly advanced malignancies.

Nancy E. Davidson, MD, a medical oncologist who has specialized in breast cancer for more than 20 years, has been elected to become president of the American Society of Clinical Oncology (ASCO) for a 1-year term beginning in June 2007. She took office as president-elect this month, during ASCO's 42nd annual meeting in Atlanta.

Data published recently in the Journal of the American Medical Association showed that in the estrogen-alone substudy of the Women's Health Initiative (WHI), conjugated estrogens at a dose of 0.625 mg did not increase breast cancer incidence in postmenopausal women.

The Journal of Clinical Oncology has published results of a large-scale trial conducted with the National Surgical Adjuvant Breast and Bowel Project (NSABP) confirming that the Oncotype DX 21-gene panel, which quantifies the risk of breast cancer recurrence, also predicts the likelihood of response to chemotherapy in a large portion of women with early-stage breast cancer. This study successfully challenges the common assumption that

The 20th anniversary feature article on "Twenty Years of Systemic Therapy for Breast Cancer" and its reviews in the January 2006 issue of ONCOLOGY are incomplete from a global perspective. I must gently protest the suggestion that the "end of breast cancer as a serious cause of human mortality is now in sight."

During the past 18 months, researchers have developed substantial evidence supporting the notion that stem cells play a critical role in the development of at least some cancers, their progression, and the prognosis of patients, including breast, brain, lung, and prostate cancer, multiple myeloma, and melanoma.

A survey of 121 breast cancer patients attending a breast cancer clinic found that 59% had received their "bad news" diagnosis over the telephone (mainly in their local area). Brianna J. Crawford, research coordinator at the Breast Diagnostic and Cancer Clinic, Mayo Clinic, Rochester, Minnesota, reported the study results in a poster session at the American Psychosocial Oncology Society (APOS) Third Annual Conference (P14-3).

Postmenopausal breast cancer patients given the intravenous bisphosphonate zoledronic acid (Zometa) twice a year at the start of adjuvant therapy with the aromatase inhibitor letrozole (Femara) had significantly increased bone mineral density (BMD) at 12 months, compared with a delayed-therapy group. Nigel Bundred, MD, of University Hospital, South Manchester, UK, presented the findings at the 5th European Breast Cancer Conference (EBBC) (abstract 12).

Raloxifene (Evista, Eli Lilly) has proven as effective as tamoxifen in reducing the risk of invasive breast cancer in postmenopausal women who are at increased risk of the disease. Initial findings from the Study of Tamoxifen and Raloxifene (STAR) showed that both drugs reduced breast cancer risk by about 50% but that patients in the raloxifene arm had 36% fewer uterine cancers and 29% fewer blood clots than those on tamoxifen.

STAR Trial Shows Raloxifene to Be as Effective as Tamoxifen in Preventing Invasive Breast Cancer

Twenty years ago, antiestrogen therapy with tamoxifen played only a secondary role in breast cancer care. All hopes to cure metastatic breast cancer were still pinned on either the discovery of new cytotoxic drugs or a dose-dense combination of available cytotoxic drugs with bone marrow transplantation. A similar strategy with combination chemotherapy was employed as an adjuvant for primary breast cancer. Simply stated, the goal was to kill the cancer with nonspecific cytotoxic drugs while keeping the patient alive with supportive care. However, medical research does not travel in straight lines, and an alternative approach emerged to solve the problem of controlling tumor growth with minimal side effects: targeted therapy. The approach of using long-term antihormone therapy to control early-stage breast cancer growth would revolutionize cancer care by targeting the tumor estrogen receptor (ER). The success of the strategy would contribute to a decrease in the national mortality figures for breast cancer. More importantly, translational research that targeted the tumor ER with a range of new antiestrogenic drugs would presage the current fashion of blocking survival pathways for the tumor by developing novel targeted treatments. But a surprise was in store when the pharmacology of "antiestrogens" was studied in detail: The nonsteroidal "antiestrogens" are selective ER modulators&#151;ie, they are antiestrogens in the breast, estrogens in the bone&#151;and they lower circulating cholesterol levels. This knowledge would establish a practical approach to breast cancer chemoprevention for women at high risk (tamoxifen) and low risk (raloxifene).

The Breast Cancer International Research Group (BCIRG) and the Sanofi-Aventis group announced the results from the first interim efficacy and updated safety analyses from the BCIRG 006 phase III breast cancer study, which show that trastuzumab (Herceptin) combined with docetaxel (Taxotere)-based regimens significantly improved disease-free survival for women with early HER2-positive breast cancer.