S8 • Clinical Breast Cancer Supplement April 2003

IntroductionEmerging Strategies in the

Management of Breast CancerJoyce A. O’Shaughnessy, MD

Supplement Editor

Breast cancer is one of the most widely investigated dis-eases of our time. Chemotherapeutic approaches to thetreatment of breast cancer have been used and extensive-ly studied since the 1970s. Over the past few years, manynew chemotherapeutic, hormonal, and biologic agentshave emerged in an ever-constant effort to improve the ef-ficacy and tolerability of treatment strategies. In additionto the advent of new drugs, new surgical approaches andscreening techniques are also helping to pave the road tobetter treatment of this disease. This supplemental issueof Clinical Breast Cancer features articles on emergingtrends in the staging and management of breast cancer byinvestigators who presented their research and insights atThe Future of Breast Cancer: An International BreastCancer Congress held in the Bahamas from July 31through August 3, 2002.

Neoadjuvant chemotherapy has historically been em-ployed for the purpose of reducing the size of cancers thatare too large for initial mastectomy or breast-conservingsurgery. Preoperative chemotherapy followed by breastcancer still poses many questions, including long-termlocal control in comparison with primary surgery and thereliability of nodal pathology at the time of surgery. Withthe emergence of new chemotherapy agents such as thetaxanes and the variety of available combinations withtraditional agents, an increasing amount of data is avail-able regarding the neoadjuvant treatment of breast can-cer. Eleftherios P. Mamounas, MD, from the AultmanHealth Foundation Cancer Center in Canton, Ohio, sum-marizes the important data available and discusses the fu-ture directions of neoadjuvant chemotherapy for breastcancer. Please see his article on pages S10-S19 for a de-tailed discussion.

Capecitabine is a relatively new agent in the arsenalagainst breast cancer that capitalizes on the overexpres-sion of thymidine phosphorylase by malignant cancercells. This enzyme is critical in the conversion of capecita-bine to the active 5-fluorouracil and is expressed in abun-dance in the tumor cell. Capecitabine is therefore prefer-entially tumor-activated and is thus associated with a

more favorable tolerability profile. The activity of capeci-tabine has been demonstrated in the metastatic settingfor both treatment-naive and previously treated patientsand is currently being investigated as part of adjuvantchemotherapy. Please see the article on pages S20-S25 foran in-depth discussion on capecitabine in breast cancer.

Since the discovery that anthracyclines have antineo-plastic activity, doxorubicin has been widely investigatedand utilized in the adjuvant treatment of breast cancer.These investigations have borne fruit because doxorubi-cin improves upon the efficacy of non–anthracycline-con-taining adjuvant regimens, albeit with some associatedcardiotoxicity and myelosuppression. Concerns surround-ing the toxicity profile of doxorubicin coupled with en-couraging efficacy provided rationale for finding alterna-tive anthracyclines with similar efficacy and improved tol-erability. Epirubicin is one such anthracycline that hasgained much attention in this arena. The comparison ofepirubicin and doxorubicin has been the focus of severaltrials and is discussed extensively by Kaklamani andGradishar on pages S26-S33.

For over 50 years, hormonal therapies have been an im-portant part of the strategy against breast cancer due tothe dependency of this disease on estrogens and andro-gens. As is seen in other tumor types with hormonal de-pendency, over time, breast cancer develops hormone-in-dependent growth, rendering hormonal therapies ineffec-tive. A greater understanding of the cellular mechanismsinvolved in the transition to hormone independence willsurely provide us with new avenues to combat this dis-ease. Human epidermal growth factor receptor–2 (HER2)is a surface molecule that has been recognized since the1980s to be a major factor in breast tumorigenesis andgrowth. Ring and Dowsett of the Royal Marsden Hospitalin London, United Kingdom, present intriguing evidencefor an additional role of HER2 in the development of hor-monal resistance in breast cancer. Their article examinesthe correlation between HER2 overexpression and re-sponse to tamoxifen in the preclinical setting as well as inthe neoadjuvant, adjuvant, and metastatic settings inorder to provide a comprehensive look at the clinical im-plications of this finding. For an in-depth discussion,please see their article on pages S34-S41.

Anastrozole is another hormonal agent that has nowbeen extensively investigated in all stages of breast cancerand has a unique mechanism of action from tamoxifen.

Address for correspondence: Joyce A. O’Shaughnessy, MD, BaylorCharles A. Sammons Cancer Center, Collins Building, 5th Floor,3535 Worth Street, Dallas, TX 75246Fax: 214-370-1850; e-mail: joyce.o’shaughnessy@usoncology.com

Baylor Charles A. Sammons Cancer Center, US Oncology, Dallas, Texas

Clinical Breast Cancer Supplement April 2003 • S9

Anastrozole clearly has a superior safety profile comparedwith tamoxifen due to the reduced risk of endometrialcancer and thromboembolic complications. A large, ran-domized, double-blind trial (the Arimidex, Tamoxifen,Alone or in Combination trial) was conducted to compareanastrozole and tamoxifen as single agents and in combi-nation in postmenopausal women with early-stage breastcancer. At 3 years’ median follow-up, the results of thistrial demonstrated superior efficacy and safety of anas-trozole compared with tamoxifen. Aman Buzdar, MD, ofthe M. D. Anderson Cancer Center in Houston, Texas, de-tails the practical implications of this trial in his article onpages S42-S48.

Nodal involvement at the time of breast cancer resec-tion provides both the oncologist and the patient with in-formation regarding the extent of disease and is valuablein guiding the selection of optimal treatment. Tradition-ally, this has been assessed by complete axillary dissec-tion, but recently, many clinicians have come to believethat sentinel lymph node biopsy provides accurate infor-mation and reduces complications that can accompanymore extensive resection. In addition, there has been con-troversy over the use of ultra-sensitive methods such as

reverse-transcriptase polymerase chain reaction and cy-tokeratin-19 staining for detecting occult metastases andthe clinical implications of such information. David M.Euhus, MD, of the University of Texas SouthwesternMedical Center in Dallas, Texas, provides an in-depth lookat sentinel lymph node dissections and the associatedmethods of detecting occult disease on pages S49-S54.

In addition to axillary lymph node biopsy, positronemission tomography (PET) scanning is also being usedincreasingly for the staging of breast cancer as well as fordiagnosis and restaging. This method has demonstratedusefulness in the detection of distant metastases and dis-ease recurrence. Wu and Gambhir discuss the current sta-tus and the pros and cons of PET scanning in the man-agement of breast cancer. Their article can be found onpages S55-S63.

Overall, I believe you will find this supplement to pro-vide excellent updates on several novel strategies current-ly being employed in the staging and management ofbreast cancer. I hope these articles provide you with use-ful clinical strategies as well as insights into future ad-vances on the horizon.