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Local Recurrence, the Augmented Breast, and the Contralateral Breast
Introduction
Over a quarter million women in the United States are diagnosed with breast cancer annually, with over 3.6 million women living with a personal history of breast cancer. Through improvements in detection, advances in adjuvant therapies, and overall increased awareness of breast cancer risk, mortality from breast cancer continues to decline. Over the past decades, treatment of breast cancer has evolved from a single radical approach to an individualized or personalized approach to treatment. Although multidisciplinary treatment continues to be the mainstay, with surgery, radiotherapy, and systemic therapy essential for cure, personalizing each treatment approach to extent of disease, biology, and future breast cancer risk is paramount. Understanding risk for both recurrence as well as future contralateral breast cancer is necessary, as treatment planning needs to focus on both curative intent for the index breast cancer as well as avenues for future breast cancer prevention in women at high risk.
As the number of women who undergo treatment for breast cancer increases, more patients will be at risk for locoregional recurrence or the development of a second primary breast cancer. Disease recurrence can be local, regional, or distant. Local recurrence refers to reappearance of the original cancer in the ipsilateral treated breast or chest wall, regional recurrence applies to the tumor recurring in the regional lymph nodes including the ipsilateral axillary, supra/infraclavicular, or internal mammary (IM) lymph nodes, and distant recurrence is disease recurrence beyond the regional nodal basin or involving other organ systems.
As important as understanding risk for locoregional recurrence is, understanding risk for contralateral breast cancer is also essential for patient education and treatment planning. Contralateral breast cancer is considered a second primary breast cancer. Contralateral breast cancer risk is multifactorial, with risk dependent on age, family history, presence of pathogenic gene mutations, as well as index cancer biology and treatment.
This chapter addresses complex conditions requiring comprehensive multidisciplinary planning and treatment, such as future breast cancer risk, both contralateral breast cancer and recurrent breast cancer. The chapter will focus on understanding personalized risk, the role for surgical risk reduction, as well as diagnostic workup and treatment algorithms for recurrent breast cancer. This chapter will also address reconstructive challenges and strategies for patients with locoregional recurrence, along with breast cancer in the augmented breast.
Future Breast Cancer Risk
Understanding risk for both new primary breast cancer as well as recurrence of diagnosed breast cancer is essential in counseling patients on treatment and strategies to reduce future risk of breast cancer. Large randomized trials have demonstrated no survival advantage to mastectomy as compared to breast conservation, giving women with early-stage disease the option for both breast conservation as well as mastectomy for breast cancer treatment. Understanding each individual’s risk for both locoregional recurrence as well as second primary cancer is important for informed patient decision making.
Cancer Risk in the Contralateral Breast
Although breast cancer risk has been discussed in Chapters 9 and 10 , this section will focus primarily on the importance of assessing personalized contralateral breast cancer risk, the role for contralateral prophylactic mastectomy, and consensus guidelines for contralateral prophylactic mastectomy recommendation.
All women diagnosed with breast cancer have an increased risk for second primary breast cancer development, with contralateral breast cancer occurring in approximately 4% to 15% of surviving breast cancer patients. This risk is demonstrated to be 1.3 to 1.9 times higher than the risk of primary breast cancer in the general population, as demonstrated in a Surveillance, Epidemiology, and End Results (SEER) registry study by Xiong and colleagues. For women in the general population, Xiong and colleagues demonstrated an overall 1.9% cumulative incidence of contralateral breast cancer incidence at 5years, 4.6% cumulative incidence at 10years, and 10.5% cumulative incidence at 20years, which places women diagnosed with breast cancer to have approximately a 0.5% annual risk of contralateral breast cancer. However, contralateral breast cancer risk is multifactorial, as it is affected by environmental factors, biochemical factors implicated in breast carcinogenesis, as well as familial and genetic factors. Annual risk is therefore patient-dependent, with rates as low as 0.2% peryear up to 4% peryear depending on individual risk factors.
Clinicopathologic factors alone are implicated in increased risk of contralateral breast cancer. The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study, a large population-based study comparing contralateral breast cancer patients with individually matched control patients with unilateral breast cancer, investigated clinicopathologic factors in contralateral breast cancer risk development, including cancer type and tumor biology. Lobular histology of the index tumor as well as estrogen receptor– and progesterone receptor–negative subtypes were shown to have higher risk of contralateral breast cancer. A recent meta-analysis by Akdeniz and colleagues also demonstrated lobular histology and estrogen receptor–negative subtype as risk factors for the development of contralateral breast cancer, in addition to body mass index (BMI ≥30 kg/m 2 ), and treatment with radiotherapy under the age of 40years. It is important to highlight that the administration of adjuvant therapies (both chemotherapy and endocrine therapy) was associated with a reduction in contralateral breast cancer risk, in addition to older age at initial breast cancer diagnosis. Considerations regarding age and adjuvant therapies are therefore important when counseling patients. Similar results demonstrated in a breast cancer study in the Netherlands also concluded that younger age is a risk factor for contralateral breast cancer, yet adjuvant therapies (both endocrine therapy and chemotherapy) decrease this risk. The role for endocrine therapy in reducing contralateral breast cancer risk was supported in the Early Breast Cancer Trialists’ Collaborative Group, which demonstrated a 47% reduction in contralateral breast cancer risk in women taking tamoxifen for 5years. To note, there was no benefit from adjuvant tamoxifen on contralateral breast cancer risk in women whose index breast cancer was estrogen receptor–negative. Reduction in risk related to endocrine therapy is supported by an early SEER database study that demonstrated a 3% peryear reduction in contralateral breast cancer incidence in the United States since 1985, thought to be related to the usage of adjuvant endocrine therapies for estrogen receptor–positive breast cancer ( Fig. 68.1 ). These studies in turn demonstrate that women in the general population have overall low risk of contralateral breast cancer, which is lowest in older women with hormone receptor–positive disease who are candidates for endocrine therapy.
Although biologic factors alone are associated with an increased development of contralateral breast cancer, family history and known inherited genetic mutations confer the highest risk for the development of a subsequent contralateral breast cancer. A strong family history of both breast and ovarian cancer alone has been shown to place women at higher risk for contralateral breast cancer, with women with first-degree relatives at a twofold higher risk. This elevated risk was demonstrated in the early WECARE study, which investigated the risk of contralateral breast cancer in women who were not carriers of BRCA1/2 mutations but had a history of cancer in first- and second-degree relatives. Risk for contralateral breast cancer was associated with degree of affected family member as well as both age at diagnosis in the cancer patient and age of diagnosis in the affected relative, with the highest risk in patients diagnosed before the age of 45years with first-degree relatives also diagnosed before the age of 45years. History of affected relatives having bilateral breast cancer was also associated with higher risk. The WECARE study also evaluated risk associated with known BRCA1/2 mutation carriers, whom have the highest risk of contralateral breast cancer ( Table 68.1 ). To further understand family history alone, the updated WECARE II study excluded patients found to have newer high-risk gene mutations in the DNA damage response genes PALB2 , CHECK2 , and ATM , as well as the known common breast cancer susceptibility gene SNPS linked to increased breast cancer risk. Study results continued to demonstrate contralateral breast cancer risk to be nearly twofold higher in women with first-degree relatives alone. The risk of contralateral breast cancer was again demonstrated to be affected by age, with the highest risk for contralateral breast cancer in women with first-degree relatives diagnosed with bilateral breast cancer under the age of 40years. In women with second-degree family history, contralateral breast cancer risk was 40% higher than that of those without a family history. Similar results have been supported in earlier studies demonstrating degree of family history as well as early-onset breast cancer diagnosis in relatives to confer higher risk for the development of contralateral breast cancer. Based on these studies, annual risk ranges from 0.5% to 2% peryear depending on age of diagnosis, degree of affected family member, and presence of bilateral disease ( Table 68.1 ).
Table 68.1
Cumulative 10-Year Risk of Contralateral Breast Cancer According to Age at First Breast Cancer Diagnosis, Family History of Breast Cancer, and Inherited Pathogenic Mutations
From Reiner AS, John EM, Brooks JD, et al. Risk of asynchronous contralateral breast cancer in noncarriers of BRCA1 and BRCA2 mutations with a family history of breast cancer: a report from the Women’s Environmental Cancer and Radiation Epidemiology Study. J Clin Oncol . 2013;31:433–439.
| NONCARRIERS WITH NO FAMILY HISTORY | NONCARRIERS WITH AFFECTED SECOND-DEGREE RELATIVE ONLY | NONCARRIERS WITH ANY AFFECTED FIRST-DEGREE RELATIVE | NONCARRIERS WITH ANY BILATERALLY AFFECTED FIRST-DEGREE RELATIVE | BRCA1 OR BRCA2 MUTATION CARRIERS b | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Age of Proband (Years) at First Diagnosis | 10-Year Cumulative Risk of CBC a (%) | 95% CI (%) | 10-Year Cumulative Risk of CBC a (%) | 95% CI (%) | 10-Year Cumulative Risk of CBC a (%) | 95% CI (%) | 10-Year Cumulative Risk of CBC a (%) | 95% CI (%) | 10-Year Cumulative Risk of CBC a (%) | 95% CI (%) |
| 25–29 | 6.3 | 4.4 to 8.7 | 8.1 | 4.5 to 14.2 | 13.4 | 7.7 to 24.5 | 21.7 | 11.1 to 42.3 | 28.2 | 16.0 to 50.0 |
| 30–34 | 7.0 | 5.4 to 8.7 | 9.0 | 5.2 to 14.9 | 14.7 | 8.9 to 25.5 | 23.7 | 12.8 to 44.2 | 30.7 | 18.4 to 51.5 |
| 35–39 | 5.2 | 4.1 to 6.3 | 6.7 | 3.9 to 11.0 | 11.1 | 6.8 to 19.1 | 18.1 | 9.8 to 33.4 | 23.7 | 14.3 to 39.3 |
| 40–44 | 4.2 | 3.3 to 5.1 | 5.4 | 3.2 to 8.9 | 9.0 | 5.5 to 15.4 | 14.8 | 8.0 to 27.2 | 19.4 | 11.8 to 32.1 |
| 45–49 | 4.5 | 4.1 to 5.6 | 6.2 | 4.4 to 9.9 | 7.5 | 5.3 to 11.9 | 15.1 | 8.2 to 27.7 | 12.2 | 6.5 to 22.9 |
| 50–54 | 4.0 | 3.6 to 4.9 | 5.5 | 3.9 to 8.8 | 6.7 | 4.7 to 10.6 | 13.4 | 7.3 to 24.7 | 10.8 | 5.8 to 20.3 |
| All ages (25–54) | 4.6 | 4.0 to 5.1 | 5.9 | 4.6 to 8.6 | 8.6 | 6.1 to 11.5 | 15.6 | 8.5 to 28.5 | 18.4 | 16.0 to 21.3 |
CBC , Contralateral breast cancer.
a Risk determined actuarially using previously described methodology combining annual SEER CBC rates and adjusted rate ratios from the Women’s Environmental Cancer and Radiation Epidemiology Study.
Although family history of breast cancer alone predisposes women to a second contralateral breast cancer, the risk is highest in patients with known inherited pathogenic germline mutations. Studies demonstrate up to a 27% risk at 5years and 43% risk at 10years depending on the specific mutation. Recent studies demonstrate BRCA1 , BRCA2 , and CHECK2 c.1100delC germline mutations to carry the greatest risk. However, the strongest data available are in patients with inherited pathogenic BRCA mutations. The WECARE study demonstrated a 10-year cumulative risk of contralateral breast cancer ranging from 10.8% to 30.7% depending on age of breast cancer diagnosis, with women under the age of 45years having a 20% to 30% risk of developing contralateral breast cancer in 10years ( Table 68.1 ). In a recent prospective study of 9856 BRCA1 and BRCA2 pathogenic mutation carriers, Kuchenbaecker and colleagues estimated the incidence of contralateral breast cancer for BRCA1 mutation carriers to be between 23 and 28 per 1000 person-years for the period of up to 20years after the first breast cancer diagnosis, with the cumulative risk of contralateral breast cancer of 40% at 20years after first diagnosis. For BRCA2 mutation carriers, the estimated contralateral breast cancer incidence was lower, between 13 and 18 per 1000 person-years during theyears after the first breast cancer diagnosis, with the cumulative risk of contralateral breast cancer of 26% at 20years after first diagnosis. The risk of contralateral breast cancer declined with increasing age at first breast cancer diagnosis for BRCA1 mutation carriers, but not BRCA2 mutation carriers. Contralateral breast cancer risk was also reduced by risk-reducing salpingo-oopherectomy. Reduction in contralateral breast cancer risk associated with risk-reducing salpingo-oopherectomy was also demonstrated by Metcalfe and colleagues, with a 59% reduction in risk of contralateral breast cancer in BRCA mutation carriers who underwent risk-reducing salpingo-oopherectomy. The reduction in risk was dependent on age, with the greatest benefit for women who underwent risk-reducing salpingo-oopherectomy prior to the age of 50years. Contralateral breast cancer risk associated with mutation in other breast cancer–associated genes such as CHEK2 , TP53 , PALB2 , ATM , and NBN is less well studied.
Rise of Contralateral Prophylactic Mastectomy
Due to increased awareness of contralateral breast cancer risk, there have been increasing rates of contralateral prophylactic mastectomies over theyears. The increase in incidence was first demonstrated by Tuttle and colleagues in a SEER database study of 152,755 breast cancer patients with stage I to III disease. Tuttle and colleagues demonstrated a doubling in the rate of contralateral prophylactic mastectomy from 1998 to 2003, with up to 11% of women at that time electing to undergo concomitant contralateral prophylactic mastectomy at the time of their index breast cancer treatment. The increase in rate was independent of stage, with an increase in contralateral prophylactic mastectomy rates in all stages I to III. A simultaneous increase in breast conservation rate was also demonstrated, suggesting that women at that time were either electing a less aggressive approach with breast conservation or the most aggressive approach with bilateral mastectomy. Similar results were demonstrated by Albornoz and colleagues in a recent National Cancer Database study of 1,856,702 women diagnosed with early stage 0 to II breast cancer from 1998 to 2011. As demonstrated in the earlier SEER study, there was an increase in contralateral prophylactic mastectomy rates, with a 14% annual increase in contralateral prophylactic mastectomy from 2005 to 2011 ( Fig. 68.2 ). Similar to the SEER study, unilateral mastectomy rates continued to decline; however, following 2005, breast conservation rates also started to decline, demonstrating that patients were favoring the most aggressive approach to breast cancer treatment and risk reduction. Kurian and colleagues demonstrated that increased use of contralateral prophylactic mastectomy was associated with younger patient age, with women <40years having the highest rate of receipt of contralateral prophylactic mastectomy. In addition to age, extent of disease, tumor biology, race, higher education, socioeconomic status, insurance carriers, use of magnetic resonance imaging (MRI), and access to reconstruction have all been associated with the rise in contralateral prophylactic mastectomy.
In addition to clinicopathologic factors and sociodemographic factors, psychological factors influence decision making. In the Young Women’s Breast Cancer Study, a prospective study of young women under the age of 40years diagnosed with stage I to III invasive breast cancer, Rosenberg and colleagues demonstrated desire for peace of mind ranked second to desire for a lower chance of getting breast cancer in the contralateral breast. Eighty-seven percent of women believed they were at an increased risk for contralateral breast cancer, and 85% desired contralateral prophylactic mastectomy to prevent breast cancer spreading to other places in the body. Ninety-four percent of the patients in this study believed that undergoing contralateral prophylactic mastectomy would improve their survival from breast cancer. In a recent study, Parker and colleagues demonstrated primary psychosocial measures of increased cancer distress, cancer worry, and body image concerns as drivers for contralateral prophylactic mastectomy in women diagnosed with unilateral, nonhereditary breast cancer. In women who appear to understand their true risk, Rendle and colleagues demonstrated that personal implications regarding risk continued to be the driving factor, with women stating that even a small absolute reduction in risk is more important than the risk of being diagnosed with breast cancer again.
Oncologic Outcomes Following Contralateral ProphylacticMastectomy
Given the rise in rates of contralateral prophylactic mastectomy and associated psychologic factors impacting patient decision making, the true oncologic benefit of contralateral prophylactic mastectomy along with risk must be understood for informed decision making. A focus on individualized contralateral breast cancer risk as discussed previously, in addition to extent of contralateral breast cancer risk reduction and impact on overall and breast cancer–specific survival, is important to discuss with each patient. Understanding oncologic outcomes aids in a comprehensive approach to counseling patients on the role for risk-reducing surgery.
Breast Cancer Risk Reduction and Survival Following Contralateral Prophylactic Mastectomy
As one would expect, studies demonstrate a universal reduction in contralateral breast cancer risk following contralateral prophylactic mastectomy, with an 86% to 100% reduction in breast cancer risk, as demonstrated in Table 68.2 . Whether the reduction in contralateral breast cancer impacts survival has been more difficult to understand, as studies are inconsistent throughout the literature given nonrandomized design, variability in survival outcome measures (overall, disease-specific, and disease-free), and many are confounded by selection bias.
Table 68.2
Studies for Contralateral Prophylactic Mastectomy Breast Cancer Risk Reduction
| Study | Year | Study Design | FU (Years) | n | Study Population | Breast Cancer Risk Reduction (%) |
|---|---|---|---|---|---|---|
| McDonnell et al. | 2001 | Case series | 10 | 745 | HBOC | 96 |
| Metcalfe et al. | 2004 | Retrospective cohort | 9.2 | 491 | BRCA | 97 |
| van Sprundel et al. | 2005 | Retrospective cohort | 3.5 | 148 | BRCA | 91 |
| Herrinton et al. | 2005 | Retrospective cohort | 5.7 | 56,400 | NA | 97 |
| Boughey et al. | 2010 | Case-control | 17.3 | 385 | HBOC | 95 |
| Bedrosian et al. | 2010 | Retrospective cohort | 6 | 311,643 | NA | 97 |
| Brewster et al. | 2012 | Retrospective cohort | 4.5 | 3889 | NA | 98 |
| Evans et al. | 2013 | Case-control | 9.7 | 698 | BRCA | 100 |
| Heemskerk-Gerritsen et al. | 2015 | Prospective cohort | 11.4 | 583 | BRCA | 90 |
An early study by Herrinton and colleagues of 56,400 women with unilateral breast cancer in a regional health system demonstrated contralateral prophylactic mastectomy to be associated with a 97% reduction in contralateral breast cancer risk and a 43% relative reduction in breast cancer–specific death compared to a matched cohort of women who did not receive contralateral prophylactic mastectomy. However, this study demonstrated a concomitant reduction in all-cause mortality, suggesting selection for a healthier cohort of patients. In a later retrospective study of patients diagnosed with clinical stage I to II breast cancer, Brewster and colleagues performed propensity matching in an attempt to adjust for bias. In multivariable analysis, contralateral prophylactic mastectomy was associated with a statistically significant improvement in both disease-free and overall survival, with the benefit greatest in patients with hormone receptor–negative disease. Although a trend toward disease-free survival persisted in women with hormone receptor–negative tumors, statistical significance was lost with propensity score-matched multivariable analysis, P =0.05. Authors concluded that length of follow-up could be attributable to lack of statistical significance, as some data suggest that survival benefit from contralateral prophylactic mastectomy would not be evident until after 10years of follow-up. Similar results were demonstrated in a SEER database study of 107,106 patients by Bedrosian and colleagues, who demonstrated reduction in disease-specific mortality in patients with estrogen receptor–negative disease who underwent contralateral prophylactic mastectomy. Patients under the age of 50years with stage I or II estrogen receptor–negative disease had a reduction in disease-specific mortality, although cancer-related survival declined with increasing age, with no improvement in patients >60years of age. The authors concluded that reduction in mortality is greatest when there is a larger absolute lifetime risk of contralateral breast cancer combined with the lowest risk of competing causes of death. The results support the established role of antiestrogen therapy in reducing contralateral breast cancer risk, as the greatest benefit was seen in women who were not candidates for endocrine therapy. Similar to other studies on survival, this study demonstrated a concomitant improvement in noncancer survival in women older than 50years, indicating that overall health status may in part contribute to the survival benefit seen in women who undergo contralateral prophylactic mastectomy. Jatoi and Parsons highlight this important limitation in a large SEER database study of 449,178 women diagnosed with stage I to III breast cancer. To investigate the effect of selection bias, their study investigated effect of receipt of contralateral prophylactic mastectomy on breast cancer–specific, all-cause, and noncancer mortality. Adjustments for age, race, AJCC stage, estrogen and progesterone receptor status, and histologic tumor grade were performed through multivariate logistic regression analysis. Results demonstrated a reduction in breast cancer–specific and all-cause mortality in patients who underwent contralateral prophylactic mastectomy; however, more importantly, a greater reduction in noncancer mortality was demonstrated, supporting selection bias of a healthier cohort of patients undergoing contralateral prophylactic mastectomy.
Studies investigating impact on survival in our highest risk patients who have a strong family history or known inherited gene mutations also demonstrate overall survival and breast cancer–specific survival benefits; however, similar concerns are raised regarding inherent selection bias. Boughey and colleagues published one of the longest follow-up studies (median follow-up of 17.3years), of 385 women with stage I to II breast cancer and a family history of breast cancer. A 95% reduction in breast cancer risk was demonstrated with an associated improvement in 10-year overall survival in women who underwent contralateral prophylactic mastectomy, which persisted in multivariate analysis. Given the retrospective nature of the study, authors did note that, short of a randomized controlled study, there always remains selection bias on part of patient and surgeon. This is also demonstrated in more recent studies investigating contralateral prophylactic mastectomy in known BRCA1/2 mutation carriers or patients with family members with known pathogenic BRCA mutations. In a prospective Dutch multicenter cohort study of BRCA mutation carriers, Heemskerk-Gerritsen and colleagues demonstrated an overall survival benefit in BRCA1/2 mutation carriers undergoing contralateral prophylactic mastectomy as compared to surveillance; however, patients undergoing contralateral prophylactic mastectomy were younger, had higher rates of risk-reducing salpingo-oopherectomy, and had higher rates of chemotherapy, all factors that are also known to influence oncologic outcomes following breast cancer treatment. Similar results from Metcalfe and colleagues demonstrated a 48% reduction in breast cancer–specific mortality following contralateral prophylactic mastectomy in 390 BRCA mutation carriers. Yet again patients undergoing contralateral prophylactic mastectomy were younger, had smaller tumor size, and had higher receipt of chemotherapy, and on propensity matching statistical significance was lost. In a retrospective analysis of BRCA1/2 mutation carriers, van Sprundel and colleagues demonstrated a 91% reduction in contralateral breast cancer risk and an overall survival benefit following contralateral prophylactic mastectomy. However, after adjustment for concomitant risk-reducing salpingo-oopherectomy, no survival benefit was observed. The effect of risk-reducing salpingo-oopherectomy was also demonstrated by Evans and colleagues of 698 BRCA1/2 pathogenic mutation carriers. In patients who underwent contralateral prophylactic mastectomy as compared to surveillance, contralateral prophylactic mastectomy was associated with an improvement in overall survival and breast cancer–specific survival in all cases compared to control-matched women for age at diagnosis and tumor stage; however, no survival benefit was seen when contralateral prophylactic mastectomy was combined with risk-reducing salpingo-oopherectomy as compared to patients who underwent risk-reducing salpingo-oopherectomy alone, demonstrating that risk-reducing salpingo-oopherectomy may play a larger role in survival in BRCA mutation carriers than contralateral prophylactic mastectomy.
Overall, studies on the oncologic benefit of contralateral prophylactic mastectomy in the general population as well as in women at high risk for breast cancer, including pathogenic BRCA mutation carriers, must be interpreted with a critical eye, as all studies are limited by nonrandomized nature, and many studies are limited by the presence of treatment-related and patient-related bias. Therefore, it is difficult to confidently conclude a direct survival benefit of contralateral prophylactic mastectomy. It is important therefore to understand and discuss available data alongside personalized risk, prognosis related to the index cancer, and the overall health of the patient, understanding that the greatest benefit would be for women with greatest absolute lifetime risk for contralateral breast cancer, lowest risk of death from the index cancer, limited competing health risks, and lack of chemoprevention options for the development of a second breast cancer.
Contralateral Prophylactic Mastectomy Guidelines
Given the complexity of the available data, contralateral risk calculators such as CBCRisk, Predict CBC, and the Manchester Guidelines for contralateral risk-reducing mastectomy have been investigated to assist providers with personalizing future risk of contralateral breast cancer and overall benefit. Leading national societies have also developed consensus statements and guidelines for clinicians on necessary counseling and personalized considerations for contralateral prophylactic mastectomy during the treatment of unilateral breast cancer ( Table 68.3 ). Consensus supports a thorough discussion of (1) individualized contralateral breast cancer risk, (2) lack of impact of contralateral prophylactic mastectomy on oncologic outcomes of the index cancer, (3) lack of 100% reduction in future cancer risk, (4) impact of bias in available studies on survival, (4) medical and psychological risks of additional surgery, and (5) alternative risk-reducing options in terms of chemoprevention and risk-reducing salpingo-oophorectomy.
Table 68.3
National Consensus Guidelines for Contralateral Prophylactic Mastectomy
| American Society of Breast Surgeons | Society of Surgical Oncology | NCCN Guidelines |
|---|---|---|
CPM should be considered for those at significant risk of CBC:
|
CPM can be considered for:
|
CPM can be considered for:
|
ADH , Atypical ductal hyperplasia; ALH , atypical lobular hyperplasia; CBC , contralateral breast cancer; CPM , contralateral prophylactic mastectomy; LCIS , lobular carcinoma in situ.
Locoregional Recurrence
Primary breast cancer recurrence also impacts decision making for breast cancer treatment. Locoregional recurrence is described as ipsilateral, in-breast recurrence following breast conservation, chest wall recurrence after mastectomy, or recurrence in the ipsilateral axillary, IM, infraclavicular, and supraclavicular lymph nodes. As stated earlier, there has been a recent trend toward increasing rates of bilateral mastectomy. This trend is occurring despite the overall improvements in survival related to early detection and advances in systemic therapies. Although oncologic outcomes following both breast conservation and mastectomy have been discussed extensively in Chapters 30 and 31 , this section will review the risk of locoregional recurrence following breast conservation and mastectomy, diagnostic workup, and the multidisciplinary management of in-breast, chest wall, and regional recurrence. The section will also as discuss treatment algorithms used for breast and chest wall reconstruction following breast cancer recurrence.
Locoregional Recurrence Risk
Landmark studies have demonstrated equivalent oncologic outcomes in terms of breast cancer survival and recurrence when comparing mastectomy to breast conservation surgery in patients with early-stage breast cancer, with the earliest studies dating back to 1970s with published 20-year follow-up. The Early Breast Cancer Trialists’ Collaborative Group meta-analysis of breast cancer trials, which involved more than 29,000 women from 36 randomized trials, demonstrated an overall lack of survival difference among women who undergo more radical surgery. This study also demonstrated that the rate of local recurrence for breast conservation patients was three times lower with the addition of adjuvant radiotherapy, with an isolated in-breast tumor recurrence rate of 6.7% after breast conservation therapy with radiation. An associated overall survival benefit concluded that one breast cancer death over the next 15 years would be avoided for every four local recurrences prevented. The addition of adjuvant radiotherapy following mastectomy has also demonstrated improvements in local recurrence and survival in high-risk women. Historically, indications for postmastectomy radiation have included four or moretumor-containing lymph nodes, tumor size 5 cm or greater, inadequate margins, or skin invasion. However, data from randomized prospective trials demonstrate that postmastectomy radiation in women with one to three positive lymph nodes improves not only local control but also survival.
Although improvements in locoregional control and survival have been demonstrated with the addition of comprehensive adjuvant radiotherapy, risk-benefit analysis must be performed. The addition of adjuvant therapies can provide benefit, but also risk overtreatment. Recently, there has been focus on deescalation of therapies. Studies investigating the role for partial breast radiotherapy techniques as well as studies investigating omission of radiation therapy in women at low risk for locoregional recurrence have been performed. A recent ASTRO consensus statement provides guidance for women “suitable” for accelerated partial breast irradiation, which is demonstrated in Table 68.4 . Additional trials investigated the ability to avoid adjuvant radiotherapy in extremely low-risk women, such as older women with early-stage breast cancer and good tumor biology. The CALGB 9343 trial, which investigated the role for radiotherapy in women 70years of age or older with early-stage estrogen receptor–positive tumors treated with lumpectomy with negative margins plus endocrine therapy without breast irradiation experience reported a 5-year locoregional recurrence rate of less than 5%. Therefore in a subset of women where the risk for locoregional recurrence is low, deescalation of adjuvant radiotherapy is an option.
Table 68.4
ASTRO Consensus Guidelines for Partial Breast Irradiation With Original and Updated Guidelines
Adapted from Correa C, Harris EE, Leonardi MC, et al. Accelerated partial breast irradiation: executive summary for the update of an ASTRO evidence-based consensus statement. Pract Radiat Oncol . 2017;7:73–79.
| Patient Group | Risk Factor | Original | Updated |
|---|---|---|---|
| Suitability |
|
|
|
| Cautionary |
|
|
40–49 years if all other criteria for “suitable” are met:
|
| Unsuitable |
|
|
|
DCIS , Ductal carcinoma in situ; EIC , extensive intraductal component; LVSI , lymphovascular space invasion.
In addition to adjuvant radiotherapy, adjuvant systemic therapies have also demonstrated improvements in locoregional control as well as overall survival. This is likely related to tumor biology. Gene expression studies have identified four major biological breast cancer subtypes: (1) luminal A (estrogen receptor–/progesterone receptor–positive, HER2-negative, low/intermediate-grade), (2) luminal B (estrogen/ progesterone receptor–positive, HER2-negative, high-grade), (3) HER2-positive, and (4) triple-negative (estrogen-, progesterone-, HER2-negative) breast cancer. These breast cancer subtypes are associated with prognosis, response to therapy, and recurrence. Some evidence suggests that molecular profiling can stratify patients with respect to locoregional recurrence more precisely than traditional determinants that focus on initial tumor burden. In a recent meta-analysis of 5418 patients undergoing mastectomy, patients with triple-negative cancers had a much higher relative risk of locoregional recurrence compared with patients with non–triple-negative cancers. Patients with HER2-positive tumors treated with the anti-HER2 monoclonal antibody trastuzumab (Herceptin) have a lower risk of locoregional recurrence. Interestingly, the fundamental difference in the risk of locoregional recurrence based on hormone receptor and HER2 status remains present even in tumors smaller than 1 cm. Time to recurrence is also correlated with breast cancer molecular subtype, with locoregional recurrence in triple-negative and HER2-overexpressing cancers occurring within the first 5years of diagnosis, and cancers with estrogen receptor expression having a more prolonged time to locoregional recurrence. However, molecular subtype should not dictate extent of surgery. Historically it was thought that cancers with more aggressive biology should be treated with more aggressive surgery, however, recent studies demonstrate that extent of surgery does not improve oncologic outcomes. In a retrospective study by Zumsteg and colleagues investigating 646 women with early-stage T1-2N0M0 triple-negative breast cancer, locoregional outcomes were comparable with breast conservation as compared to mastectomy, with a 5-year cumulative incidence of locoregional recurrence of 4.2% in patients undergoing breast conservation as compared to 5.4% undergoing mastectomy. There was no significant difference in locoregional recurrence, distant metastasis, overall recurrence, disease-free survival, or overall survival between the groups on multivariate analysis.
The incidence of recurrence and timing of recurrence are dependent on extent of disease, tumor biology, and type of surgery. The majority of chest wall recurrences appear within the first 2years after mastectomy with 90% ocurring within 5years. Chest wall recurrences are typically detected on clinical examination. Whereas local recurrences after lumpectomy are detected solely by mammography in approximately 40% to 75% of cases, by physical examination alone in 10% to 30%,by a combination of mammography and physical examination in 10% to 25%, and by other imaging modalities such as MRI in 5%. In general, locoregional recurrence after breast conservation has a better prognosis than recurrence after mastectomy, with an overall 5-year survival rate of approximately 35% from the time of recurrence after mastectomy. Timing of recurrence in breast conservation appears to be radiation-dependent. In the 20-year follow-up data from the National Surgical Adjuvant Breast and Bowel Project Protocol B-06, the local recurrence rate was 39% for lumpectomy alone but decreased to 14% when lumpectomy was followed by radiation therapy. Women who received radiation had recurrences later in their postoperative course, with 31% developing recurrence after 10years. These data are in contrast to the lumpectomy-only group, with 73% of local recurrences occurring within the first 5years after surgery. The majority of local recurrences in the ipsilateral breast after breast-conserving surgery occur in the proximity of the primary excision, whereas second primary cancers develop in other breast quadrants. If the initial tumor was an invasive cancer, then the majority of subsequent recurrences will be invasive, however, if the initial tumor was noninvasive or in situ cancer, then 50% of the recurrences will be invasive, and the remainder will be noninvasive recurrences.
The rate of local recurrence has been shown to be dependent on a multitude of factors, including patient age, tumor size, stage, grade, method of detection, and family history. In patients receiving preoperative chemotherapy, poor clinical response and residual axillary disease after chemotherapy have also been shown to be independent predictors of local recurrence. Other factors that may favor recurrence after lumpectomy include positive surgical margins at the time of lumpectomy, lymphatic invasion, associated in situ disease in the surrounding parenchyma, tumor necrosis, invasive lobular phenotype, inadequate radiation dose, and a delay of radiation therapy after lumpectomy. Because many of these variables are interrelated, it is difficult to establish independent prognostic factors for local recurrence. In addition, studies that attempt to identify risk factors for local recurrence after breast conservation suffer from patient heterogeneity and treatment selection biases. A published report from a consensus panel convened by the Society of Surgical Oncology and the American Society for Radiation Oncology states that “no ink on tumor” should be the standard pathologic margin assessment for patients treated with breast conservation therapy. This recommendation was based on a meta-analysis of 33 studies, with a median follow-up of more than 6.5years, where a positive margin defined “as ink on tumor” was associated with a greater than twofold increase in the risk of local recurrence. Interestingly, wider margins were not associated with a lower recurrence rate. It is also important to ensure that all suspicious microcalcifications have been removed on postexcision mammography before administering radiation therapy. If margins are positive or close, factors to consider when contemplating reexcision include patient age, the extent of the close margin (focal vs. diffuse disease), differences between radiographic and pathologic tumor size, and the morbidity involved with a reexcision lumpectomy, all of which should be discussed at a multidisciplinary tumor board.
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