Tracking 35 Years of Progress Against Breast Cancer

In this issue of ONCOLOGY we honor and celebrate the career and contributions of Martin D. Abeloff, MD, who died last year. Marty saw his first patient with breast cancer in 1972 and cared for his last such patient shortly before his death in 2007. Over this 35-year period much has changed in the field of breast cancer, and it is a fitting tribute to Marty that we reflect on our progress and successes and consider our challenges.

In 1972 breast cancer was the leading cause of death from malignancy for women in the United States. By 1987 lung cancer eclipsed breast cancer, in large part because of increased incidence of that commonly fatal disease, a tragedy that persists today. But in the 1990s mortality from breast cancer also began to drop, a testimony to the increased impact of screening mammography and improved therapy for breast cancer. Although still the most common non–skin cancer diagnosis in US women, women diagnosed with breast cancer often receive treatment and live to succumb to another illness. What has changed over this time?

Good medicine is inextricably linked to good science. Modern molecular and cellular biology have blossomed over these decades and helped us to identify the hallmarks of malignancy. Thus, we know today that breast cancer, like other cancers, is the result of an accumulation of genetic and epigenetic alterations in the cancer cell. Comprehensive sequencing of DNA from invasive primary breast cancers has shown that a dozen or more such mutations are found in any single breast cancer, and these changes may encompass a large number of genes. Global analysis of the transcriptome, proteome, kinome, and metabolome will continue to enlarge our understanding of progression from normal to malignant and inevitably lead to refinements in how we manage breast cancer. These scientific advances have already led to changes in our approach to risk assessment, prevention, and treatment.

The science of clinical investigation has also evolved. In no field of oncology has the power of the properly conducted clinical trial contributed more than in breast cancer. Virtually all counsel that we provide to patients today is derived from evidence-based medicine, the direct result of a robust system of clinical investigation.

Risk Assessment

By 1972 classical epidemiology studies had identified major risk factors for breast cancer including gender, age, reproductive factors, and family history. Over the ensuing years, two areas of progress in this area are noteworthy. The first is the understanding that a small number of women suffer from heritable breast cancer because of germ-line mutations in the BRCA1 or BRCA2 genes. Over a period of less than 20 years these two critical genes were identified, and strategies for counseling, testing, and managing mutation carriers have been identified. Testing for such mutations in high-risk individuals is now a part of routine medical care in the US. In recent years large-scale molecular studies have begun to identify lower-penetrance but more pervasive changes-like single-nucleotide polymorphisms-that are associated with increased risk of a smaller magnitude. Harnessing this knowledge will be a challenge over the next decade.

Careful clinical study has also led to the identification of other nongenetic risk factors including hormone replacement therapy. Initially thought to be a favorable general health intervention for the postmenopausal woman, it seems likely that long-term hormone replacement therapy contributes to breast cancer risk. Indeed, the abandonment of this approach for many postmenopausal women has been reported to be linked to decreased incidence of breast cancer in the US since 2002. An association between breast cancer risk and alcohol consumption has also been identified. Finally, the emerging connection between postmenopausal obesity and breast cancer gives cause for concern in the future, given the trend toward obesity in the American population.

Screening and Diagnosis

In 1972 breast cancer was frequently diagnosed because of clinical signs and symptoms. Thanks to the advent and adoption of screening mammography, the breast cancer of today is often radiologically detected and clinically occult. Ductal carcinoma in situ, an uncommon diagnosis 35 years ago, now accounts for about 20% of breast cancers in the US. Early-stage breast cancers (stage 0–II) comprise the great majority of breast cancers. The diagnosis of breast cancer has moved from surgical biopsy in the operating room to image-guided fine-needle aspiration or core biopsy in the radiology department. The use of magnetic resonance imaging (MRI) to screen women who are at especially high risk for developing breast cancer (eg, those with BRCA1 or BRCA2 mutations) is emerging.

Evaluation of imaging of all types-mammography, sonography, MRI, functional, etc-for early diagnosis continues. In addition, the possibility that ductal or mammary cell–based assays or even blood-based assays might contribute to risk assessment or early detection is now an area of serious investigation. In our zeal to improve on mammography, which detects about 85% of breast cancers, we should not abandon the principles of clinical investigation that are crucial to validating a screening approach as a means of improving overall health outcomes.

Local Therapy

In no dimension of breast cancer is the progress between 1972 and 2007 more literally visible than local therapy. An evolution of understanding breast cancer as both a local and systemic disease, coupled with results from six groundbreaking clinical trials that unequivocally demonstrated an identical survival for women with early breast cancer who undergo modified radical mastectomy or breast-conservation therapy (lumpectomy plus breast radiotherapy), truly revolutionized local therapy for breast cancer. Today studies are focused on the minimum intervention needed to achieve local control-lumpectomy in place of mastectomy, sentinel node biopsy in place of routine axillary dissection, partial rather than whole breast irradiation, image-guided radiotherapy planning to maximize benefit and minimize toxicity. For those women who require or desire mastectomy, the opportunity to pursue breast reconstruction using implants or autologous tissue at any point during the breast cancer continuum is generally recognized.

Systemic Therapy

Use of systemic therapy in breast cancer has exploded over the past 35 years. It is a rare individual with the diagnosis of breast cancer who is not offered the opportunity to receive systemic therapy. This reflects the identification of multiple drugs that can palliate symptoms of advanced breast cancer and recognition of the systemic aspects of breast cancer even at seemingly early stages, leading to the use of these agents in the adjuvant or neoadjuvant settings.

In 1972 the use of chemotherapy for advanced breast cancer was established, and results of pathbreaking adjuvant chemotherapy trials would emerge within a few short years. Multiple cytotoxic agents are now recognized as active against breast cancer, including alkylators, antimetabolites, topoisomerase inhibitors, and microtubule-targeted agents. Their application in the setting of early breast cancer has been and continues to be carefully evaluated, and the success of these approaches has been documented through individual clinical trials as well as successive meta-analyses of the worldwide experience of randomized investigations.

In addition, attention to supportive care measures such as highly effective antiemetics made these interventions safe and tolerable. This led to the 2000 National Institutes of Health consensus recommendation that adjuvant chemotherapy should be considered for women with invasive tumors greater than 1 cm in size. Today we are working to refine this recommendation by identifying women who benefit most from chemotherapy through evaluation of features of the tumor, eg, multigene assays like Oncotype Dx. This will inevitably lead to a reduction in the use of chemotherapy, likely without a worsening of clinical outcomes.

The 1970s also saw the introduction of the first targeted agent for breast cancer, tamoxifen. Over 3 decades we have identified its primary target, the estrogen receptor–signaling pathway, and demonstrated the value of this agent in women of all ages and with all stages of breast cancer, from ductal carcinoma in situ to metastatic disease. An exhaustive study of estrogen signaling led to the identification of estrogen-­deprivation strategies as alternative endocrine approaches. Thus, the role of aromatase inhibitors in postmenopausal women and ovarian ablation or suppression through luteinizing hormone-releasing hormone agonists for premenopausal women has emerged.

Two pivotal observations about hormonal therapy have come to light. First the utility of these approaches is limited to women whose tumors express the estrogen receptor alpha and/or progesterone protein. Testing of primary tumor tissue for these proteins is the norm to guide endocrine therapy selection. Second, the optimal duration of such therapies for early breast cancer is measured in years. As with chemotherapy, these principles have become clear because of randomized clinical trials and meta-analysis of worldwide results.

Tenets learned in the identification and application of endocrine therapy accelerated the development of a second type of targeted therapy for breast cancer-agents that are directed against the HER family of receptors. Recognition in 1987 that the HER2 protein is overexpressed in a subset of breast cancers with functional consequences led to the development of a monoclonal antibody against HER2, trastuzumab (Herceptin).

Three factors-the availability of tests to identify such tumors, identification of an active and safe therapeutic agent, and clinical trial data showing that administration of trastuzumab with chemotherapy to women with advanced breast cancer that overexpresses HER2 improved survival-enabled the rapid performance of adjuvant trials around the globe. These trials showed that trastuzumab appears to halve breast cancer recurrence in HER2 overexpressors. Thus, this agent went from approval by the US Food and Drug Administration for treatment of metastatic breast cancer in 1998 to approval for adjuvant therapy in 2006, a direct consequence of lessons garnered from the investigation of tamoxifen. It is certain that development of other targeted agents like lapatinib (Tykerb), ­bevacizumab (Avastin), and many more to come will be even more efficient as a result of this experience.

Prevention

The possibility that breast cancer can in some cases be prevented has also come to light over the past 3 decades. For women with BRCA1 or BRCA2 mutations, the utility of prophylactic mastectomy and/or oophorectomy is now openly discussed. For women at high risk by standard tools like the Gail model, a role for risk reduction with tamoxifen for women over 35 years of age or raloxifene (Evista) for postmenopaual women has been established through randomized trials. Important challenges remain, including adoption of these proven interventions by high-risk women because of concerns about risk-benefit balance. Ways to enhance risk assessment, development of low-toxicity approaches, and education of consumers and health-care providers will continue to be key in this endeavor.

Public Awareness and Advocacy

In 1972 breast cancer was a disease of whispers. Two influential public figures, Betty Ford and Nancy Reagan, who went public with their diagnoses, contributed enormously to the visibility of breast cancer. Individual patients also worked to influence breast cancer treatment, among them Rose Kushner, who championed the move from single-step surgery-surgical biopsy followed by immediate mastectomy-to a two-step sequence of biopsy for diagnosis followed by patient-physician consultation about definitive local therapy. The imperative for multidisciplinary care that is patient-centered became obvious and accepted. Patients and physicians embraced clinical research as a way to propel progress in the field. The importance of public awareness and the power of advocacy in advancing breast cancer management is undeniable. The contribution of federal and private financial support of breast cancer research is also palpable.

What Next?

Had Marty Abeloff not succumbed to a premature death at age 65 from leukemia and lymphoma, what might he have seen over the next 20 years? I believe that the themes of the past 35 years will continue to dominate. Foremost among these is the concept that optimal treatment of breast cancer will be grounded in an understanding of the unique features of the tumor and the host. It is hoped that the hard-learned lessons of tamoxifen and trastuzumab will be remembered and new conceptual breakthroughs to identify other targets, biomarkers, and clinical testing scenarios will continue to appear. The evolution in thinking from maximally tolerated therapy to minimal therapy needed for maximal efficacy should continue to prevail. Enhanced attention to early detection will go forward. Also important are the lessons from our colleagues working in cardiovascular and infectious diseases about the importance of risk assessment and prevention.

Ultimately, however, progress against breast cancer will require two other critical things. The first is continued investment in the scientific and clinical trial enterprise. The velocity of our progress is imperiled today by decreased funding that leads inevitably to less discovery and less opportunity for translation of the fruits of discovery into clinical investigation and application. Second, no scientific or clinical advance can be of any value if it cannot be disseminated globally and equitably to individuals in need who will profit from that advance. Thus, universal access to care through evidence-based medicine should be a goal for all of us. I know that Marty Abeloff would agree.

-Nancy E. Davidson, MD