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Breast Cancer: Stages I-II
Key Points
Patient Selection
The majority of individuals with stages I-II invasive breast cancer are candidates for breast-conserving therapy (BCT). Treatment with conservative surgery (CS) and radiotherapy (RT) is absolutely or relatively contraindicated owing to toxicity concerns for only a few patients. The anticipated cosmetic results of CS and RT may be so poor for some individuals that mastectomy with immediate reconstruction is a more appealing alternative. Pretreatment evaluation is a critical factor in deciding on the most appropriate treatment approach. Careful physical examination should be performed. All patients should have mammograms before biopsy and, in selected patients, after surgery to ensure the completeness of resection. The role of magnetic resonance imaging is still unsettled and controversial. Specimen radiography should be performed routinely, including for patients who present with a nonpalpable mass without microcalcifications. Careful pathological evaluation of the tumor specimen is mandatory, especially with regard to the margins of resection. The pathologist should note whether and how far tumor extends beyond the edges of any grossly apparent mass and whether calcifications are associated with the tumor, benign tissue, or both. Detailed description of the size of the invasive component, histological type, presence of an extensive intraductal component or lymphovascular invasion, grade, and other features of the lesion should be recorded.
Treatment
Some patients have a low risk of local recurrence when treated with CS and endocrine therapy without irradiation. However, there is no consensus on exactly which combination of patient, clinical, and histological factors permit acceptable results with this approach. There is no consensus on the minimum microscopic tumor-free margin width needed to offer patients BCT either with or without RT. Though uninvolved margins are preferred, selected patients with involved margins have excellent local control with RT. Most patients with uninvolved margins have excellent local control and cosmetic results when given whole-breast doses of approximately 45 to 50 Gy in 1.8- to 2-Gy fractions or its hypofractionated biological equivalent. Patients younger than 50 years old or those with certain histological findings may benefit most from the addition of a boost dose to the tumor bed and surrounding area. Computed tomography-guided simulation and three-dimensional treatment planning and compensation improve the homogeneity of the dose distribution and results in fewer acute side effects and improved cosmetic outcome for many patients. They should be used routinely. Accelerated partial-breast irradiation allows patients to undergo BCT more quickly than with conventional whole-breast irradiation. However, there are substantial uncertainties regarding selection of patients for this approach and its technical details. The value of RT directed at regional lymph nodes is uncertain. There is no consensus on when (and which) regional nodes should be irradiated.
Follow-Up
The focus of follow-up should be on detecting potentially curable recurrences and new primary tumors in the ipsilateral and contralateral breasts. The optimal follow-up schedule and testing regimen is unknown. Nonetheless, it is reasonable to perform biannual or annual physical examinations and annual mammograms indefinitely.
Therapy of Locoregional Recurrence
Most patients with a local recurrence who have received prior RT should undergo mastectomy. Selected patients may have acceptable results with further BCT if careful clinical, radiological, and pathological evaluation show the lesion to be limited in extent and there is no evidence of multicentric disease. Patients not previously irradiated are usually candidates for further BCT, including RT. The value of further adjuvant systemic therapy for patients with local recurrence after BCT is uncertain.
Introduction
Approximately 70% to 80% of patients with stage I or II invasive breast cancers are technically candidates for breast-conserving therapy (BCT). Six major randomized trials using modern radiotherapy (RT) techniques ( eTable 73.1 ) and a meta-analysis including additional studies found no differences in disease-free survival (DFS) or overall survival (OS) between mastectomy and BCT.
eTABLE 73.1
Randomized Trials Comparing Mastectomy to Breast-Conserving Therapy
| Trial | Dates | No. Patients | FU (y) | Time-Point (y) | DISTANT FAILURE | OVERALL SURVIVAL | ||
|---|---|---|---|---|---|---|---|---|
| M | BCT | M | BCT | |||||
| WHO | 1972-1979 | 179 | 22 (mean) | — | 0.7 (0.4-1.2) a | 0.7 (0.5-1.1) a | ||
| Milan I | 1973-1980 | 701 | 20 | 20 | 24% b | 23% b | 41% | 42% |
| NSABP B-06 | 1976-1984 | 1406 | 20.7 (mean) | 20 | 51% | 54% | 47% | 46% |
| US NCI | 1979-1989 | 279 | 25.7 | 20 | 29% c | 56% c | 44% | 38% |
| EORTC 10801 | 1980-1986 | 903 | 22.1 | 20 | 43% | 47% | 45% | 40% |
| Denmark 82TM | 1983-1989 | 731 | 19.6 | 10/20 | 61% c | 60% c | 51% | 58% |
Notes: Follow-up is median, unless otherwise noted. Rates given are actuarial, at time point indicated, unless otherwise noted. For the NSABP B-06 trial, comparison included only lumpectomy patients receiving radiotherapy.
BCT, Breast-conserving therapy (included radiotherapy); EORTC, European Organization for Research and Treatment of Cancer; FU, mean or median length of follow-up, in months; M, mastectomy; NSABP, National Surgical Adjuvant Bowel and Breast Project; US NCI, United States National Cancer Institute; WHO, World Health Organization.
a Odds ratio, BCT to mastectomy, with 95% confidence interval; exact rates not given, although illustrated in figures.
c Total relapse rate; distant metastasis rate not given separately.
Many questions remain regarding optimal patient evaluation and selection for BCT, RT techniques and doses, factors affecting complications and cosmetic outcome, follow-up, and treatment of locoregional recurrences. Several texts discuss these topics in greater depth.
Pretreatment Evaluation
Imaging
Mammography should always be performed. Magnetic resonance imaging (MRI) finds additional ipsilateral foci in 5% to 10% of candidates for BCT and unsuspected contralateral disease in 3% to 5%. Three randomized trials and several retrospective studies disagreed on whether preoperative MRI reduced the need for reexcision. MRI may be most valuable for patients with tumors larger than 2 cm or infiltrating lobular histology.
Postoperative mammograms rarely showed residual calcifications or additional masses in patients with uninvolved microscopic margins in most series, though others found higher rates. Its use did not reduce local recurrence in two series. Postoperative MRI has limited accuracy in detecting residual disease.
Pathological Evaluation
The most common approach for microscopic margin assessment for single specimens is to roll them in India ink and sequentially section perpendicularly to the long axis (“bread-loafing”). Some pathologists “shave” each face of a specimen; the margin is considered involved when tumor is seen in one of the shaved margin slides. These approaches may have quite different clinical implications. Some surgeons take additional “cavity shave” specimens after removing the main specimen. The role of intraoperative margin assessment is uncertain.
Surgical Techniques
Breast-Conserving Surgery
Detailed technical aspects of breast surgery are discussed elsewhere. Using cavity shave margins reduces the chance of margin involvement but may impair cosmetic results. Some patients may benefit from “oncoplastic” reconstruction. Simultaneous reduction mammoplasty may reduce the risk of retraction and increase satisfaction rates for patients with very large breasts and does not increase local recurrence.
Axillary Dissection
The classical three anatomic “levels” of the axilla are: level 1, lateral and inferior to the border of the pectoralis minor muscle; level 2, under the pectoralis minor; and level 3 (also called the “infraclavicular” nodes), medial and superior to the border of the pectoralis minor. Randomized trials found no differences in axillary failure or survival rates between “limited” axillary dissection (AxD; removal of level 1 or levels 1 and 2 nodes only) and “complete” AxD (removal of levels 1, 2, and 3), but limited AxD caused less morbidity.
Sentinel Node Biopsy
Sentinel node biopsy (SNB) uses injection of a radionuclide tracer or vital dye (or both) in the breast to guide the surgeon to the nodes to remove. Immediate and long-term complications are lower for SNB than for AxD. False-negative rates of SNB range from 0% to 12%, but the risk of axillary failure after a negative SNB is very small. OS and distant failure rates are the same after AxD and SNB for patients with clinically negative axillary nodes.
Breast-Conserving Surgery With Radiotherapy
The effectiveness and toxicities of BCT are affected by patient, clinical, and pathological factors and treatment parameters.
Patient Factors
Pregnancy
Unterminated pregnancy is an absolute contraindication to breast RT because of the possible teratogenic and carcinogenic effects of scattered radiation on the fetus.
Prior Treatment with Radiotherapy
There were no unusual acute or chronic sequelae in several small studies of women treated with CS and whole-breast or partial-breast RT after RT for Hodgkin disease or non-Hodgkin lymphoma, though severe soft-tissue necrosis was reported in one patient. However, these patients often decide to have mastectomies because of their substantial risk of developing future breast cancers.
Rheumatological Disorders
Three small studies found no clear increased risk of complications in patients with rheumatological disorders to a matched “normal” population, except for scleroderma. However, a study of four patients with sclerodema treated from 1998 to 2010 found no serious acute or chronic complications.
Breast Size
Women with large breasts have more acute skin reactions and long-term retraction and fibrosis than patients with smaller breasts. However, their results can be improved by technical means (see later discussion) and are generally acceptable.
Prior Breast Augmentation
Capsular fibrosis and other complications after RT occurred in half or more of patients with prior augmentation implants in two series but were much less common in several others. Thus, it seems reasonable to offer such patients BCT.
Patient Age
Patients younger than 35 to 40 years old at diagnosis have higher local recurrence rates than older patients in most series. However, their overall outcome is not superior after mastectomy. Some studies have suggested that margins smaller than 2 mm or high histological grade increase young patients’ risk of local recurrence, but other studies have not. Systemic therapy substantially reduces their local failure rates. Older patients tolerate RT well and have excellent local control rates.
Genetic Factors
A family history of breast cancer by itself does not increase the risk of local failure following BCT ( eTable 73.2 ). Most but not all studies also found modest or no differences between patients with BRCA1-2 mutations and unaffected patients (see eTable 73.2 ). Tamoxifen or oophorectomy may reduce both ipsilateral local failure and contralateral new primary cancers.
eTABLE 73.2
Local Failure Rates after Breast-Conserving Therapy in Patients with Hereditary Breast Cancer
From Recht A. Radiation Therapy and Hereditary Breast Cancer . ASCO Educational Book. Alexandria, VA: American Society of Clinical Oncology; 2010: 16-18.
| Location, Years | Risk Factor | Follow-Up (mo) | Calculation | LF: HBC | LF: Sporadic |
|---|---|---|---|---|---|
| Brisbane, 1982-1989 | Any FH | 50 | 5-year | 4% (85) | 5% (418) |
| Philadelphia, 1977-1986 | Any FH | 60 | 5-year | 6% (264) | 9% (517) |
| Houston, 1970-1994 | Any FH | 106 | Crude LRF | 10% (32/308) | 12% (80/677) |
| Chicago, 1977-1993 | 1st degree FH | 46 (mean) | 5-y | 5% (134) | 3% (660) |
| Boston, 1968-1986 (age < 36 y) | 1st degree: BC age < 50 y or OC any age | 60 (min) | 5-y Crude | 3% (1/29) | 14% (24/172) |
| Rotterdam, 1980-2001 | BRCA1 | 61 | 5-y | 12% (76) | 14% (241) |
| New York, 1989-1999 | BRCA1/2 | 50 | Crude LRF | 19% (4/21) | 6% (13/220) |
| Rotterdam, 1980-? | BRCA1/2 | 52/61 | 5-y | BRCA1 : 12% (76); BRCA2 : 17% (35) |
12% (410) b |
| Montréal, 1986-1995 | BRCA1/2 | 77 | 5-y | 6% (32 a ) | 7% (170 a ) |
| Multicenter,? | BRCA1/2 | 95/80 | 10-y | 12% (160) | 9% (445) b |
| 15-y | 24% | 17% | |||
| Paris, 1981-2000 | BRCA1/2 | 105 | Crude | 24% (7/29) | 19% (52/271) |
| Villejuif,? | BRCA1/2 | 114 | 10-y | BRCA1 : 9% (37) BRCA2 : 37% (16) |
12% (43) |
| New York-Montréal, 1980-1995 | BRCA1/2 | 116 | 10-y | 12% (57) | 8% (440) |
| New York, 1980-1990 | BRCA1/2 | 124 (survivors) | 5-y | 15% (28) | 5% (277) |
| 10-y | 22% | 7% | |||
| New Haven, 1975-1998 (age < 42 y) | BRCA1/2 | 152 (mean) | 5-y | 22% (22) | 15% (105) |
| 10-y | 41% | 19% | |||
| Heidelberg, 1995-2002 | CHEK2 | 87 | Crude | 12% (3/25) | 8% (10/125) |
Notes: Follow-up is median, unless otherwise noted. Number of patients in group in parentheses when actuarial failure rate given.
?, Not reported or unknown; FH, family history of breast cancer, unless otherwise stated; LF, local failure; LRF, locoregional failure; min, minimum potential follow-up time; OC, ovarian cancer.
a Includes patients with mastectomy; 94% of patients in series treated with breast-conserving therapy, but exact number per risk group not reported.
b Sporadic cohort matched to hereditary breast cancer cohort by age and date of diagnosis.
Long-term outcomes after ipsilateral mastectomy are the same as after BCT for patients with BRCA1-2 mutations or a family history of breast cancer in most studies, though not all. However, these studies usually contain small numbers, have considerable treatment selection bias, and short follow-up. The survival value of contralateral prophylactic mastectomy is very uncertain.
Syndromes causing impaired radiation damage repair, such as ataxia telangiectasia, result in a substantial risk of complications from RT. However, patients heterozygous for BRCA1-2 mutations or with a single ATM mutation do not have increased toxicities. Some studies suggested increased adverse results for patients with more than one ATM mutation, those with particular single ATM mutations, and those with polymorphisms of multiple radiation repair genes. Decreased RT-induced CD8 T-cell apoptosis may be a marker of late fibrosis.
In-field cancers have been reported within a few years of RT in several patients with TP53 mutations, which causes the Li-Fraumeni syndrome. Radiotherapy does not increase contralateral breast cancer rates in patients with BRCA1-2 mutations or ATM mutations in most studies, though this may depend on the specific ATM mutation.
Clinical Factors
Means of Detection
Local recurrence rates are similar for patients with palpable and nonpalpable cancers. Patients with nipple discharge do not have higher local failure rates.
Tumor Size and Location
Tumor size does not affect local recurrence rates. However, neoadjuvant therapy is usually needed to achieve both acceptable cosmetic results and negative margins in most patients with tumors larger than 4 to 5 cm.
Patients with subareolar or periareolar lesions that do not directly extend to the nipple or areola have high local control rates following excision with negative margins without nipple-areolar resection. Local control is high even when nipple-areolar resection must be performed.
Bilateral Breast Cancers
Patients with bilateral breast cancer (either synchronous or metachronous) can be treated successfully with BCT without increased complications.
Multiple Ipsilateral Primary Cancers
Multiple synchronous ipsilateral breast cancers occur in only 2% to 4% of patients. Local failure rates are similar to those of patients with a single lesion when negative margins are achieved.
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