LESS SURGERY FOR BREAST CANCER DIAGNOSIS AND TREATMENT

Kelly Hunt, MD, MD Anderson Cancer Center, Houston, Texas, USA, presented “50 Years of Surgery for Breast Cancer: Doing Less?” Radical mastectomy was the surgical standard of care for over a century before the National Surgical Adjuvant Breast and Bowel Project B-04 trial (NSABP B-04) randomly assigned women with operable breast cancer and clinically positive nodes to radical mastectomy or total mastectomy plus RT and women with clinically negative nodes to one of these treatments or to total mastectomy without RT [Fisher B et al. N Engl J Med 2002]. After 25 years of follow-up, there was no difference in survival among treatments, and women with node-negative breast cancer survived longer than those with node-positive cancer.

This resulted in total (modified radical) mastectomy's replacing radical mastectomy as the standard of care. Subsequent trials compared total mastectomy plus axillary lymph node dissection (ALND) against lumpectomy with ALND or lumpectomy with ALND and RT. In a representative trial, NSABP B-06, there was no difference in disease-free survival, distant disease-free survival, or overall survival among treatment groups throughout 25 years of follow-up, indicating that breast conserving treatment is equivalent to mastectomy [Fisher B et al. N Engl J Med 2002].

ALND is still used despite the lack of evidence that it improves survival and its association with serious complications such as lymphedema. Sentinel lymph node dissection (SLND) is more selective, removing only the node or nodes that receive direct lymphatic drainage from the primary tumor site. NSABP B-32 [Krag DN et al. Lancet Oncol 2007] showed no differences in overall survival, disease-free survival, or local-regional disease recurrence with SLND only versus SLND plus ALND after 10 years of follow-up [J Clin Oncol 2013; Krag DN et al. Lancet Oncol 2010], making SLND the preferred method of axillary evaluation for patients with clinically node-negative disease. Ongoing trials comparing axillary RT with ALND plus RT or evaluating the addition of regional node RT will contribute to the more precise use of surgery on the basis of disease response to therapy.

INCREASING IMPORTANCE OF RADIATION THERAPY

Jay R. Harris, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, USA, presented “50 Years of Radiotherapy for Breast Cancer: Doing More?” pointing out that 50 years ago, RT after mastectomy for patients with high-risk disease was so crude that cardiac adverse effects canceled out any potential clinical gains. Now breast-conserving surgery plus RT has become an alternative to mastectomy, with similar rates of local recurrence after 10 years of follow-up, and breast RT plus SLND has become an alternative to ALND. The use of systemic therapy has increased the efficacy and importance of RT by addressing micrometastatic disease.

RT needs to be safer because irradiation of the heart results in premature ischemic heart disease. A recent case-controlled study showed that major coronary events increased with mean heart dose with no threshold [Darby SC et al. N Engl J Med 2013]. This risk started within the first 5 years of therapy and continued into the third decade after RT and was greater for those with preexisting cardiac risk factors. Current technology makes it possible to keep the mean heart dose at <1 Gy for almost all those with node-negative disease and <2 Gy for those requiring postmastectomy RT, which should keep the risk low compared with the survival benefit. Hypofractionation of breast RT, in which larger doses are given less often, is being explored for improved patient convenience and cosmetic results, lower rates of local recurrence, and potentially lower cost of therapy.

PATIENT-TAILORED SYSTEMIC THERAPY

In addition to “50 Years of Advances in Breast Cancer Treatment: What Have We Learned? Where Are We Going?” Dr. Burstein also presented “50 Years of Systemic Therapy for Breast Cancer: From One Size Fits All to Tailored Therapy.” Systemic therapy makes local therapy more effective because it reduces local recurrence after breast-conserving surgery and RT; downstages tumors to make breast-conserving surgery feasible; reduces the need for ALND, making SNLD possible; and improves survival after local-regional recurrence. Effective therapy for early breast cancer relies on adjuvant chemotherapy. Advances in therapy have included the use of aromatase inhibitors and tamoxifen to decrease disease recurrence. The discovery of human epidermal receptor 2 (HER2) amplification in some breast cancers resulted in the development of trastuzumab, the first targeted therapy for breast cancer, which has altered the natural history of breast cancer and led to current guidelines recommending HER2 testing for all patients. Since the first reports of the successful use of trastuzumab as adjuvant therapy [Romond et al. N Engl J Med 2005], additional targeted therapies addressing HER2 oncogene addiction and driver mutations at different stages of breast cancer have been developed.

Decision making for adjuvant therapy has shifted from a stage- and risk-informed process to one that considers tumor biology, including estrogen receptor and HER2 status.

Endocrine treatment options have been included in updated American Society of Clinical Oncology guidelines [Burstein HJ et al. J Clin Oncol 2014]. For those patients with favorable profiles (ie, HER2 negative, estrogen receptor positive), it remains controversial who should receive chemotherapy, and this will be evaluated in clinical trials.

Despite the advances in breast cancer therapy, particularly for early-stage disease, and improvements in diagnosis, challenges remain. Among these are finding critical mutations to target, particularly in triple-negative disease, given that known mutations are present only in a minority of tumors; improving on treatment for patients with metastatic disease; providing better palliative care; and caring for patients in the current and evolving health care environment. It will also be challenging to integrate genomic medicine into standard therapy while the era of personalized and precision medicine is still in its infancy.