Breast-Conserving Therapy for Invasive Breast Cancers

Introduction

Breast conservation has been the standard alternative to mastectomy for most patients with early-stage invasive breast cancer for decades. The purpose of breast-conserving surgery (BCS) is the removal of all gross disease from the breast, and as much microscopic disease as possible, without compromising a good cosmetic result. Residual minimal microscopic disease may then be eliminated by postoperative radiation therapy (RT) with higher tumor control but moderate doses compared to what would be required to treat gross or extensive microscopic residual disease. In this way, the combination of a moderate surgery with a moderate dose of radiation could together result in equal disease control, better cosmetic outcome, and reduced toxicity compared to a more extensive surgery or high-dose radiation. Historically, since mastectomy itself was the original form of whole breast treatment, it made sense to replace it with radiation that was also directed to the entire preserved breast—whole-breast radiation therapy (WBRT). This was also supported by pathologic studies analyzing the likelihood and extent of residual microscopic disease in the breast after a BCS. In this way, the combination of BCS and WBRT became the standard alternative to mastectomy. The large majority of women presenting with early-stage invasive breast cancer are eligible for BCS and WBRT, with equal long-term survival as mastectomy. And due to modern patient selection and multidisciplinary treatment, BCS and WBRT can now result in equally low rates of local recurrence in the preserved breast compared with the chest wall or reconstructed breast after mastectomy.

This chapter examines the patient selection and outcomes of BCS and WBRT for patients with invasive breast cancer and clinically early-stage I and II disease. The use of hypofractionation that shortens overall number of treatments needed and other practical aspects of dose delivery for WBRT are discussed. Additional sections cover the use of a tumor bed boost with WBRT, integration of WBRT with systemic therapy, management of a local recurrence in a breast previously treated by BCS and WBRT, and when BCS alone without RT at all may be safely offered to selected patients. In other chapters, issues related to regional lymph node irradiation and partial breast irradiation will be covered.

Breast-Conserving Surgery and Radiation Therapy as an Alternative to Mastectomy

Randomized prospective clinical trials that enrolled patients from 1972 to 1989 confirmed that BCS and WBRT are associated with equal distant disease-free survival and overall survival as mastectomy for patients with stage I to II invasive breast cancer even 20 years or more after initial treatment. In fact, the original NCI consensus statement in 1991 used language stating that breast conservation was not only an option but preferable compared to mastectomy at that time. The equivalence of these two options is universally accepted by the international oncology community. Moreover, in population-based studies performed since the randomized trials were conducted, BCS and WBRT has been associated with superior breast cancer–specific survival compared to mastectomy in certain subgroups of early-staged patients. For these reasons, WBRT has been and remains the standard alternative to mastectomy after BCS.

The randomized prospective phase III trials from an earlier era (before 1990) showed that BCS and WBRT, even when resulting in high rates of local recurrence >15%, could still yield comparable long-term survival for patients with early-stage breast cancer. But this does not mean that local control should be considered unimportant. These trials were not powered to detect any small differences in survival that could result from higher local recurrence rates. The Early Breast Cancer Trialists’ Collaborative Group meta-analysis of randomized trials in the setting of BCS has shown that, as differences in local control rates between two treatments increase, differences in survival can eventually become apparent. Therefore the goal of BCS and WBRT should be to closely match or even equal the rates of ipsilateral breast tumor recurrence (IBTR) of a mastectomy. An IBTR is to be avoided because it is associated with additional morbidity of treatment, patient distress associated with return of the cancer, and a possibility that recurrence is not always salvaged and could increase chances for ultimate death from disease. But improvements since 1990 in multidisciplinary management that incorporates a team of diagnostic imaging, surgery, pathology, radiation, and medical oncology have resulted in a notable drop of the risk for IBTR with BCS and WBRT to rates <5% at 10 years in the past decade ( Fig. 47.1 and Table 47.1 ).

In retrospect, the very high risks of an IBTR after BCS and WBRT in those phase III trials from decades ago would be considered unacceptable compared to the very low observed rates of IBTR today. This apparent improvement in local control after WBRT has occurred while using comparable doses of radiation then and now—a dose equivalent of 50 Gy with or without a 10 Gy tumor bed boost was the same in 1985 as it was in 2015. This improved local control for radiation that is caused by changes in external factors to the treatment itself may be considered alike to the Will Rogers phenomenon of improved survival by stage migration and new diagnostic techniques. The phase III trials of BCS and WBRT were conducted prior to 1990 and do not represent modern patient selection and multidisciplinary treatment. For example, compared to today’s standards, there was suboptimal preoperative imaging compared with modern mammography, ultrasound, and MRI that may have understaged extensive or multicentric breast cancers particularly in women with dense breast tissue; less effective surgical-pathologic correlation to imaging findings particularly for the nonpalpable mass in an era before modern localization procedures; absence of comprehensive pathologic margin assessment and confirmation of a negative margin after BCS; less effective or underutilized systemic therapy compared with modern systemic and targeted therapies; and inclusion of women who may have been at higher risk for new primaries (but counted as IBTR) due to lack of BRCA mutation testing in that era. All of these factors combine to make patients going into their WBRT today after BCS with or without adjuvant systemic therapy much more likely to have better local control outcomes.

Patient Selection for Breast-Conserving Surgery and Whole Breast Radiation

The overwhelming majority of patients presenting with stage I to II breast cancer are eligible for WBRT due to the wide inclusivity based on clinical and pathologic criteria ( Table 47.2 ). This is in contrast to alternatives to WBRT such as accelerated partial breast irradiation (APBI) or BCS alone, each of which has a long list of eligibility restrictions based on age, tumor size, receptor status, node status, or need to have endocrine therapy. In order to be eligible for WBRT as an alternative to mastectomy, patients can be of almost any age ≥18 years. BCS is typically limited to patients with tumors approximately 4 to 5 cm so that a resection to negative margins can be achieved with a good cosmetic result, but women with larger breast sizes may be able to undergo BCS with an even larger clinical tumor size. Any histology of invasive carcinoma, grade, and receptor subtype defined by hormone receptor or HER2 expression are permissible. Associated ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), atypical ductal hyperplasia (ADH), other benign proliferative breast changes or presence of lymphatic invasion in the surrounding breast tissue apart from the primary invasive tumor are acceptable. Patients can have disease limited to the breast only with negative axillary nodes or have minimal disease of one to two sentinel lymph nodes with or without microscopic extranodal extension and remain eligible for WBRT. For patients with more extensive nodal disease, extensive extranodal extension, or who are high-risk node-negative, BCS and WBRT are not excluded but may need to be combined with regional node RT. Any size of surgical cavity, small or large, is permitted for WBRT, and it is not necessary to be able to precisely define the exact extent of the lumpectomy cavity during RT planning as is the case with APBI. However, these factors may limit the ability to deliver a tumor bed boost with WBRT.

There are many relative contraindications to WBRT that are not always contraindications to BCS when mitigated appropriately or when the patient is adequately accepting of the risks. Patients with initial tumor size greater than 5 cm, or tumors less than 5 cm with a large size relative to their breast size ratio, are best considered for neoadjuvant chemotherapy for tumor downstaging. Patients who respond well may become better candidates for BCS and WBRT. Marking the tumor location by a clip before neoadjuvant therapy is recommended to localize the area if there is a good response and to ensure negative margins. Clinically or radiologically detected multifocal disease (defined as having two or more tumors in the same quadrant) can be treated with BCS if done through a single incision with an acceptable cosmetic result to the patient. Similarly, patients with a subareolar tumor location requiring sacrifice of the nipple-areolar complex, or women with small breast size and/or a large visible volume deficit from BCS, may still prefer breast conservation over mastectomy when the subsequent cosmetic appearance is still acceptable to them. A focally positive margin after BCS, particularly when at an anatomic boundary like skin or posterior fascia, is acceptable for WBRT in many cases and may be amenable to a tumor bed boost. An extensive intraductal component (EIC) is defined as the simultaneous presence of intraductal carcinoma which comprises a prominent portion of the area of the primary mass (generally 25% or more) and of intraductal carcinoma clearly extending beyond the infiltrating margin of the tumor or present in sections of grossly normal adjacent breast tissue. The presence of an EIC-positive tumor in pathology studies has been associated with an increase residual burden of disease, and a greater preponderance for DCIS extension farther from the primary invasive tumor mass. For this reason, an EIC is a cautionary finding for partial breast radiation or BCS alone without radiation, but not for WBRT when a negative margin is obtained. While RT should not be given during pregnancy, a BCS could be done during pregnancy with WBRT delayed until after delivery. BRCA -associated breast cancer may be appropriately treated with BCS and WBRT with high rates of local control, but the patient could be at increased risk for subsequent new primary breast cancers in the preserved breast tissue so must be counseled on need for risk reduction treatments and enhanced screening. Other relative contraindications to breast conservation due to potential for increased toxicity with WBRT include a history of collagen vascular disease (scleroderma or active lupus with skin involvement, but not rheumatoid arthritis) or Li-Fraumeni syndrome (increased risk for RT-related malignancy).

There are relatively few factors that alone or in combination with other factors should exclude a patient altogether from BCS and/or WBRT. These include patients whose risk of IBTR after WBRT based on one or more combination of factors is expected to be high and markedly greater than mastectomy, and patients who may have unacceptable risk for complications from WBRT. Extensively positive margins on breast tissue after multiple attempts at BCS is an indication for mastectomy. For patients with initial tumor size greater than 5 cm who are not good candidates or do not respond to neoadjuvant chemotherapy, BCS also may be contraindicated. True gross multicentric disease (two or more tumors clinically or radiologically presenting in separate quadrants), or diffuse biopsy-proven malignant calcifications that cannot be removed by BCS, remain indications for mastectomy in most cases. An extensive extent of disease, by imaging or physical examination, that could not be resected to a negative margin and/or leave an acceptable cosmetic result at the judgment of the surgeon are also indications for mastectomy. Due to concerns about potential toxicity of whole-breast re-irradiation, breast cancer in a breast previously exposed to significant amounts of radiation, either for prior breast cancer or other malignancy like Hodgkin’s, that will require repeat WBRT after a second BCS is also contraindicated. These patients may be eligible for other options for breast conservation (see Management of Local Failure After Breast-Conserving Surgery and Radiation Therapy mentioned later).

Sections mentioned later give additional detail to key factors that are the most significant for special consideration during patient selection and predicting local outcome after BCS and WBRT.