Is a higher boost dose of radiation necessary after breast-conserving therapy for patients with breast cancer with final close or positive margins?

To determine rates of loco-regional recurrence (LRR), distant failure and overall survival for patients with breast cancer treated with breast-conserving therapy (BCT) with a close or positive surgical margin (C/PM) treated with standard dose boost radiation compared with a higher boost of radiation. We retrospectively studied 1476 patients with T1-T3 invasive breast cancer treated with BCT between 1992 and 2009. Median age was 57 years. Patients were divided into three groups: Group I included 1197 patients (81 %) with negative margins who received a standard boost (median 60 Gy) total dose to the lumpectomy cavity; Group II included 116 patients (8 %) with C/PM who received a standard boost (median 60 Gy); and Group III included 163 patients (11 %) with C/PM who received a higher boost (median 68 Gy). Biological subtypes (e.g., ER, PR, HER2/neu) were available for 858 patients (58 %) and were also assessed for any relationship to LRR rate. The Kaplan-Meier, Cox-regression, and log-rank tests were used to estimate rates of LRR and the significance of risk factors. Median follow-up was 8.6 years. The overall 5- and 10-year cumulative incidences of LRR were 2.1 % (95 % CI 0.8-2.1 %) and 4.5 % (95 % CI 3.4-6.0 %), respectively. The 5- and 10-year cumulative incidences of LRR for Group I (negative margins + standard boost) were 1.9 and 4.4 %; for Group II (C/PM + standard boost) were 3.9 and 7.0 %; and for Group III (C/PM + higher boost) were 2.9 and 3.8 %, respectively. No statistically significant differences in LRR rates were found among the three groups (p = 0.4). Similar results were obtained for distant failure (p = 0.3) and overall survival (p = 0.4). On multivariate analysis, tumor grade (p = 0.03), systemic-therapy (p = 0.005), node positivity (p = 0.05), young age (p = 0.001), and biological subtype (p = 0.04) were statistically significantly associated with higher LRR. Higher boost dose and margin positivity were not significant. Our data suggest that the 10-year risk of local recurrence for patients with close or positive margins receiving a standard boost was 7 % compared to 3.8 % for those receiving a higher boost; however, this difference was not significant. A higher boost dose did not significantly improve local control, nor did margins impact LRR risk in our cohort of patients.

Long-term outcomes among breast cancer patients with extensive regional lymph node involvement: implications for locoregional management.

Extensive lymph node (LN) involvement portends significant risk for distant metastasis (DM) among breast cancer patients. As a result, local management may be of secondary import to systemic control in this population. We analyzed patients with ≥10 involved LNs (N3) to evaluate the feasibility of breast conserving therapy (BCT) vs modified radical mastectomy (MRM) in this high-risk cohort. Among 98 women with N3 disease 46 (46.9%) underwent BCT and 52 (53.1%) received MRM. Nearly all patients (92%) received comprehensive radiotherapy (RT) including axillary and supraclavicular fields. The Kaplan-Meier method and Cox regression analyses were used to analyze time-to-event outcomes. Median follow-up was 76 months, with a 5-year DFS of 64.9% and OS of 71.9% among the cohort. Poorly differentiated (p = 0.007), ER-negative tumors (p = 0.015) had adverse DFS outcomes. Treatment groups did not differ with regard to 10-year DFS (45.4% for MRM vs. 57.6% for BCT; p = 0.31), or OS (61.4 vs. 63.7%; p = 0.79). DM-free survival was 48.9% following MRM and 60.6% following BCT (p = 0.19). Patients with ≥10 involved LNs have similar outcomes following BCT or MRM, suggesting that RT may obviate the need for more-extensive surgery. While local control is comparably favorable regardless of surgical approach, systemic control remains a challenge in this population.

The impact of isolated tumor cells on loco-regional recurrence in breast cancer patients treated with breast-conserving treatment or mastectomy without post-mastectomy radiation therapy.

To compare the outcome of patients with invasive breast cancer, who had isolated tumor cells (ITC) in sentinel lymph nodes, pN0(i+), to patients with histologically negative nodes, pN0. We retrospectively studied 1,273 patients diagnosed with T1-T3 breast cancer from 1999 to 2009. Patients were divided into 2 populations: 807 patients treated with breast-conserving surgery (BCS) and radiotherapy (RT), 85(10.5 %) with pN0(i+) and 722(89.5 %) with pN0. And the other population had 466 patients treated with mastectomy without post-mastectomy radiation therapy (PMRT), 80(17.2 %) with pN0(i+),and 386(82.8 %)with pN0. All patients underwent sentinel node biopsy, and the presence of ITC was determined. Patients with axillary dissection only or neoadjuvant chemotherapy were excluded. Among the 1,273 patients studied; 87.3 % received adjuvant systemic therapy. Kaplan-Meier, Cox regression, and log-rank statistical tests were used. Median patient age was 55.7 years. Median follow-up was 69.5 months. The 5- and 10-year cumulative incidence of Loco-regional recurrence (LRR) for patients treated with BCS and RT was 1.6 and 3.5 % for 85 pN0(i+) patients, and 2.4 and 5 % for 722 pN0 patients, respectively. For patients treated with mastectomy without PMRT, 5- and 10-year LRR rates were 2.8 and 2.8 % for 80 pN0(i+) patients, and 1.8 and 3 % for 386 pN0 patients, respectively. There were no statistically significant differences in LRR (p = 0.9), distant recurrence (p = 0.3) ,and overall survival (p = 0.5) among all groups. On multivariate analysis, ITC were not associated with increased risk of LRR, distant recurrence and overall survival. Grade (p = 0.003) and systemic therapy (p = 0.02) were statistically significantly associated with risk of LRR. Sentinel node ITC have no significant impact on LRR, distant recurrence and overall survival in breast cancer patients. Additional treatments such as axillary dissection, chemotherapy, or regional radiation should not be given solely based on the presence of sentinel node ITC.

Brain metastases after breast-conserving therapy and systemic therapy: incidence and characteristics by biologic subtype.

The characteristics of brain metastases (BM) that develop after breast-conserving therapy (BCT) for early-stage breast cancer (BC) remain incompletely defined. We examined 1,434 consecutive patients with stage I/II invasive BC who received BCT from 1997 to 2006, 91 % of whom received adjuvant systemic therapy, according to BC subtype. Median follow-up was 85 months. Overall 5-year cumulative incidence of BM was 1.7 %; 0.1 % for luminal A, 3.3 % for luminal B, 3.2 % for luminal-HER2, 3.7 % for HER2, and 7.4 % for triple negative (TN). Women who developed BM were more likely at BC diagnosis to be younger (P < .0001) and have node-positive (P < .0001), grade 3 (P < .0001), hormone receptor-negative (P = .006), and HER2-positive (P = .01) tumors. Median time from BC diagnosis to BM was 51.4 months (range, 7.6-108 months), which was longer among luminal versus non-luminal subtypes (P = .0002; median, 61.4 vs. 34.5 months). Thirty-four percent of patients who developed distant metastases (DM) eventually developed BM. Median time from DM to BM was 12.8 months but varied by subtype, including 7.4 months for TN, 9.6 months for luminal B, and 27.1 months for HER2. Eighty-one percent of all BM patients presented with neurologic symptoms. Median number of BM at diagnosis was two, and median BM size was 15 mm, with TN (27 mm) and luminal B (16 mm) exhibiting the largest median sizes. In conclusion, the risk of BM after BCT varies significantly by subtype. Given the large size and symptomatic presentation among luminal B and TN subtypes, earlier BM detection might improve quality of life or increase eligibility for non-invasive treatments including stereotactic radiosurgery. Women with DM from these two BC subtypes have a high incidence of BM with a short latency, suggesting an ideal target population for trials evaluating the utility of MRI screening.

Clinical outcome of isolated locoregional recurrence in patients with breast cancer according to their primary local treatment.

INTRODUCTION: This study assessed the clinical outcome and prognostic factors in patients with breast cancer who presented with isolated locoregional recurrence (ILRR) as a first event. MATERIALS AND METHODS: Between 1970 and 2008, 2960 patients with pT1-2, N0-3, M0 primary invasive breast cancer had either breast-conserving therapy (BCT) using lumpectomy and radiation therapy (RT) (group A = 1849 patients) or mastectomy without RT (group B = 1111 patients). Out of groups A and B, 117 and 103 patients, respectively, developed ILRR as a first event. Those 220 patients served as the basis for this study. A multivariate analysis was performed to estimate the clinical outcome of both groups, taking into account clinically relevant variables for the primary tumor and ILRR. RESULTS: The median follow-up after ILRR was 83 months. The median disease-free interval (DFI) was 79 and 38 months for groups A and B, respectively. The overall survival (OS) for group A was 81% and 69% at 5 and 8 years, respectively. For group B, it was 61% and 46%, respectively. The distant metastasis-free survival (DMFS) for group A was 84% at 5 years and remained 84% at 8 years. The DMFS for group B was 60% at 5 years and 52% at 8 years. In multivariate analysis, initial local treatment (BCT vs. mastectomy without RT), pathologic T stage, locoregional recurrence site (local vs. regional), and DFI (≤ 4 years vs. > 4 years) were significant prognostic variables for both OS and DMFS. CONCLUSION: Patients with breast cancer who developed ILRR after BCT as their initial local treatment have better clinical outcome compared with those who had mastectomy without RT.

Risk of local failure in breast cancer patients with lobular carcinoma in situ at the final surgical margins: is re-excision necessary?

PURPOSE: To compare the outcome of patients with invasive breast cancer both with and without lobular carcinoma in situ (LCIS)-positive/close surgical margins after breast-conserving treatment. METHODS AND MATERIALS: We retrospectively studied 2358 patients with T1-T2 invasive breast cancer treated with lumpectomy and radiation therapy from January 1980 to December 2009. Median age was 57 years (range, 24-91 years). There were 82 patients (3.5%) with positive/close LCIS margins (<0.2 cm) and 2232 patients (95.7%) with negative margins. A total of 1789 patients (76%) had negative lymph nodes. Patients who received neoadjuvant chemotherapy were excluded. A total of 1783 patients (76%) received adjuvant systemic therapy. Multivariable analysis (MVA) was performed using Cox's proportional hazards model. RESULTS: The 5-year cumulative incidence of locoregional recurrence (LRR) was 3.2% (95% confidence interval [CI] 2.5%-4.1%) for the 2232 patients with LCIS-negative surgical margins (median follow-up 104 months) and 2.8% (95% CI 0.7%-10.8%) for the 82 patients with LCIS-positive/close surgical margins (median follow-up 90 months). This was not statistically significant (P=.5). On MVA, LCIS-positive margins after the final surgery were not associated with increased risk of LRR (hazard ratio [HR] 3.4, 95% CI 0.5-24.5, P=.2). Statistically significant prognostic variables on Cox's MVA for risk of LRR included systemic therapy (HR 0.5, 95% CI 0.33-0.75, P=.001), number of positive lymph nodes (HR 1.11, 95% CI 1.05-1.18, P=.001), menopausal status (HR 0.96, 95% CI 0.95-0.98, P=.001), and histopathologic grade (grade 3 vs grade 1/2) (HR 2.6, 95% CI 1.4-4.7, P=.003). CONCLUSION: Our results suggest that the presence of LCIS at the surgical margin after lumpectomy does not increase the risk of LRR or the final outcome. These findings suggest that re-excision or mastectomy in patients with LCIS-positive/close final surgical margins is unnecessary.

Circulating tumor cells as predictors of response and failure in breast cancer patients treated with preoperative chemotherapy.

AIM: To explore the significance of circulating tumor cells (CTCs) detection in the course of preoperative chemotherapy (PC) and their effect on the outcomes.
 METHODS: Fifty-five patients with stage II/III invasive breast cancer were enrolled into a preoperative clinical trial. Patients were given PC with sequential single-agent doxorubicin and paclitaxel vs paclitaxel followed by doxorubicin. Blood samples (8 mL) were collected from patients before PC, after each phase, and at 6 months intervals during follow-up. Peripheral blood mononuclear cells were isolated and enriched for epithelial cells. Quantitative RT-PCR was used to determine the presence of cytokeratin 19 (CK19) mRNA. Samples were considered positive when the PCR curve crossed the standard threshold curve.
 RESULTS: After the first phase of chemotherapy, there was a 59% overall reduction in the median tumor volume. The percentage of volume reduction did not differ between patients who presented with detectable CTCs at baseline and those who did not (p=0.89). After the second phase of chemotherapy, there was a further decrease in the median tumor volume to 93% from baseline. There was no correlation between the lack of response and the presence of CTCs either after the first (p=0.36) or second (p=0.5391) phases of PC. The presence of CTCs was a predictor of local or distant relapse (p=0.0411). The detection of CTCs did not affect overall survival (p=0.2569).
 CONCLUSION: CTCs can be used as predictors of relapse after definitive treatment of locally advanced breast cancer; however, CTCs detection in peripheral blood during the course of PC does not implicate a particular pattern of response to treatment.

Basal subtype of invasive breast cancer is associated with a higher risk of true recurrence after conventional breast-conserving therapy.

PURPOSE: To determine whether breast cancer subtype is associated with patterns of ipsilateral breast tumor recurrence (IBTR), either true recurrence (TR) or elsewhere local recurrence (ELR), among women with pT1-T2 invasive breast cancer (IBC) who receive breast-conserving therapy (BCT). METHODS AND MATERIALS: From Jan 1998 to Dec 2003, 1,223 women with pT1-T2N0-3 IBC were treated with BCT (lumpectomy plus whole-breast radiation). Ninety percent of patients received adjuvant systemic therapy, but none received trastuzumab. Biologic cancer subtypes were approximated by determining estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), and human epidermal growth factor receptor-2-positive (HER-2+) expression, classified as luminal A (ER+ or PR+ and HER-2 negative [HER-2-]), luminal B (ER+ or PR+ and HER-2+), HER-2 (ER- and PR- and HER-2+), and basal (ER- and PR- and HER-2- ) subtypes. Imaging, pathology, and operative reports were reviewed by two physicians independently, including an attending breast radiologist. Readers were blinded to subtype and outcome. TR was defined as IBTR within the same quadrant and within 3 cm of the primary tumor. All others were defined as ELR. RESULTS: At a median follow-up of 70 months, 24 patients developed IBTR (5-year cumulative incidence of 1.6%), including 15 TR and 9 ELR patients. At 5 years, basal (4.4%) and HER-2 (9%) subtypes had a significantly higher incidence of TR than luminal B (1.2%) and luminal A (0.2%) subtypes (p < 0.0001). On multivariate analysis, basal subtype (hazard ratio [HR], 4.8, p = 0.01), younger age at diagnosis (HR, 0.97; p = 0.05), and increasing tumor size (HR, 2.1; p = 0.04) were independent predictors of TR. Only younger age (HR, 0.95; p = 0.01) significantly predicted for ELR. CONCLUSIONS: Basal and HER-2 subtypes are significantly associated with higher rates of TR among women with pT1-T2 IBC after BCT. Younger age predicts for both TR and ELR. Strategies to reduce TR in basal breast cancers, such as increased boost doses, concomitant radiation and chemotherapy, or targeted therapy agents, should be explored.

External beam accelerated partial-breast irradiation using 32 gy in 8 twice-daily fractions: 5-year results of a prospective study.

PURPOSE: External beam accelerated partial breast irradiation (APBI) is an increasingly popular technique for treatment of patients with early stage breast cancer following breast-conserving surgery. Here we present 5-year results of a prospective trial. METHODS AND MATERIALS: From October 2003 through November 2005, 98 evaluable patients with stage I breast cancer were enrolled in the first dose step (32 Gy delivered in 8 twice-daily fractions) of a prospective, multi-institutional, dose escalation clinical trial of 3-dimensional conformal external beam APBI (3D-APBI). Median age was 61 years; median tumor size was 0.8 cm; 89% of tumors were estrogen receptor positive; 10% had a triple-negative phenotype; and 1% had a HER-2-positive subtype. Median follow-up was 71 months (range, 2-88 months; interquartile range, 64-75 months). RESULTS: Five patients developed ipsilateral breast tumor recurrence (IBTR), for a 5-year actuarial IBTR rate of 5% (95% confidence interval [CI], 1%-10%). Three of these cases occurred in patients with triple-negative disease and 2 in non-triple-negative patients, for 5-year actuarial IBTR rates of 33% (95% CI, 0%-57%) and 2% (95% CI, 0%-6%; P<.0001), respectively. On multivariable analysis, triple-negative phenotype was the only predictor of IBTR, with borderline statistical significance after adjusting for tumor grade (P=.0537). CONCLUSIONS: Overall outcomes were excellent, particularly for patients with estrogen receptor-positive disease. Patients in this study with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI. Larger, prospective 3D-APBI clinical trials should continue to evaluate the effect of hormone receptor phenotype on IBTR rates.

Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy.

PURPOSE: Prior results of breast-conserving therapy (BCT) have shown substantial rates of local recurrence (LR) in young patients with breast cancer (BC). PATIENTS AND METHODS: We studied 1,434 consecutive patients with invasive BC who received BCT from December 1997 to July 2006. Ninety-one percent received adjuvant systemic therapy; no patients received trastuzumab. Five BC subtypes were approximated: estrogen receptor (ER) or progesterone receptor (PR) positive, HER2 negative, and grades 1 to 2 (ie, luminal A); ER positive or PR positive, HER2 negative, and grade 3 (ie, luminal B); ER or PR positive, and HER2 positive (ie, luminal HER2); ER negative, PR negative, and HER2 positive (ie, HER2); and ER negative, PR negative, and HER2 negative (ie, triple negative). Actuarial rates of LR were calculated by using the Kaplan-Meier method. RESULTS: Median follow-up was 85 months. Overall 5-year cumulative incidence of LR was 2.1% (95% CI, 1.4% to 3.0%). The 5-year cumulative incidence of LR was 5.0% (95% CI, 3.0% to 8.3%) for age quartile 23 to 46 years; 2.2% (95% CI, 1.0% to 4.6%) for ages 47 to 54 years; 0.9% (95% CI, 0.3% to 2.6%) for ages 55 to 63 years; and 0.6% (95% CI, 0.1% to 2.2%) for ages 64 to 88 years. The 5-year cumulative incidence of LR was 0.8% (95% CI, 0.4% to 1.8%) for luminal A; 2.3% (95% CI, 0.8% to 5.9%) for luminal B; 1.1% (95% CI, 0.2% 7.4%) for luminal HER2; 10.8% (95% CI, 4.6% to 24.4%) for HER2; and 6.7% (95% CI, 3.6% to 12.2%) for triple negative. On multivariable analysis, increasing age was associated with decreased risk of LR (adjusted hazard ratio, 0.97; 95% CI, 0.94 to 0.99; P = .009). CONCLUSION: In the era of systemic therapy and BC subtyping, age remains an independent prognostic factor after BCT. However, the risk of LR for young women appears acceptably low.

Chest wall radiotherapy: middle ground for treatment of patients with one to three positive lymph nodes after mastectomy.

PURPOSE: To evaluate the outcomes for patients with Stage II breast cancer and one to three positive lymph nodes after mastectomy who were treated with observation or adjuvant radiotherapy to the chest wall (CW) with or without the regional lymphatics. METHODS AND MATERIALS: We retrospectively analyzed 238 patients with Stage II breast cancer (one to three positive lymph nodes) treated with mastectomy at the Massachusetts General Hospital between 1990 and 2004. The estimates of locoregional recurrence (LRR), disease-free survival (DFS), and overall survival were analyzed according to the delivery of radiotherapy and multiple prognostic factors. RESULTS: LRR and DFS were significantly improved by postmastectomy radiotherapy (PMRT), with a 5- and 10-year LRR rate without PMRT of 6% and 11%, respectively and, with PMRT, of 0% at both 5 and 10 years (p = .02). The 5- and 10-year DFS rate without PMRT was 85% and 75%, respectively, and, with PMRT, was 93% at both 5 and 10 years (p = .03). A similar benefit was found for patients treated with RT to the CW alone. The LRR, DFS, and overall survival rate for patients treated to the CW only was 0%, 96%, and 95% at 10 years, respectively. CONCLUSION: Our data suggest that adjuvant PMRT to the CW alone provides excellent disease control for patients with breast cancer <5 cm with one to three positive lymph nodes.

Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy.

PURPOSE: To determine whether breast cancer subtype is associated with outcome after breast-conserving therapy (BCT) consisting of lumpectomy and radiation therapy. PATIENTS AND METHODS: We studied 793 consecutive patients with invasive breast cancer who received BCT from July 1998 to December 2001. Among them, 97% had pathologically negative margins of resection, and 90% received adjuvant systemic therapy. No patient received adjuvant trastuzumab. Receptor status was used to approximate subtype: estrogen receptor (ER) or progesterone receptor (PR) positive and human epidermal growth factor receptor 2 negative = luminal A; ER+ or PR+ and HER-2+ = luminal B; ER-and PR -and HER-2+ = HER-2; and ER-and PR -and HER-2-= basal. Competing risks methodology was used to analyze time to local recurrence and distant metastases. RESULTS: Median follow-up was 70 months. The overall 5-year cumulative incidence of local recurrence was 1.8% (95% CI, 1.0 to 3.1); 0.8% (0.3, 2.2) for luminal A, 1.5% (0.2, 10) for luminal B, 8.4% (2.2, 30) for HER-2, and 7.1% (3.0, 16) for basal. On multivariable analysis (MVA) with luminal A as baseline, HER-2 (adjusted hazard ratio [AHR] = 9.2; 95% CI, 1.6 to 51; P = .012) and basal (AHR = 7.1; 95% CI, 1.6 to 31; P = .009) subtypes were associated with increased local recurrence. On MVA, luminal B (AHR = 2.9; 95% CI, 1.3 to 6.5; P = .007) and basal (AHR = 2.3; 95% CI, 1.1 to 5.2; P = .035) were associated with increased distant metastases. CONCLUSION: Overall, the 5-year local recurrence rate after BCT was low, but varied by subtype as approximated using ER, PR, and HER-2 status. Local recurrence was particularly low for the luminal A subtype, but was less than 10% at 5 years for all subtypes. Although further follow-up is needed, these results may be useful in counseling patients about their anticipated outcome after BCT.