Rita F. Abi Raad

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.

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.

Primary breast lymphoma: Patient profile, outcome and prognostic factors. A multicentre Rare Cancer Network study

BackgroundTo asses the clinical profile, treatment outcome and prognostic factors in primary breast lymphoma (PBL).MethodsBetween 1970 and 2000, 84 consecutive patients with PBL were treated in 20 institutions of the Rare Cancer Network. Forty-six patients had Ann Arbor stage IE, 33 stage IIE, 1 stage IIIE, 2 stage IVE and 2 an unknown stage. Twenty-one underwent a mastectomy, 39 conservative surgery and 23 biopsy; 51 received radiotherapy (RT) with (n = 37) or without (n = 14) chemotherapy. Median RT dose was 40 Gy (range 12–55 Gy).ResultsTen (12%) patients progressed locally and 43 (55%) had a systemic relapse. Central nervous system (CNS) was the site of relapse in 12 (14%) cases. The 5-yr overall survival, lymphoma-specific survival, disease-free survival and local control rates were 53%, 59%, 41% and 87% respectively. In the univariate analyses, favorable prognostic factors were early stage, conservative surgery, RT administration and combined modality treatment. Multivariate analysis showed that early stage and the use of RT were favorable prognostic factors.ConclusionThe outcome of PBL is fair. Local control is excellent with RT or combined modality treatment but systemic relapses, including that in the CNS, occurs frequently.

Validation of a Web-Based Predictive Nomogram for Ipsilateral Breast Tumor Recurrence After Breast Conserving Therapy

PURPOSE IBTR! version 1.0 is a web-based tool that uses literature-derived relative risk ratios for seven clinicopathologic variables to predict ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT). Preliminary testing demonstrated over-estimation in high-risk subgroups. This study uses two independent population-based datasets to create and validate a modified nomogram, IBTR! version 2.0. METHODS Cox regression modeling was performed on 7,811 patients treated with BCT at the British Columbia Cancer Agency (median follow-up, 9.4 years). Population-based hazard ratios were generated for the seven variables in the original nomogram. A modified nomogram was then tested against 664 patients from Massachusetts General Hospital (median follow-up, 9.3 years). The mean predicted and observed 10-year estimates were compared for the entire cohort and for four groups predefined by nomogram-predicted risks: group 1: less than 3%; group 2: 3% to 5%; group 3: 5% to 10%; and group 4: more than 10%. Results IBTR! version 2.0 predicted an overall 10-year IBTR estimate of 4.0% (95% CI, 3.8 to 4.2), while the observed estimate was 2.8% (95% CI, 1.6 to 4.7; P = .10). The predicted and observed IBTR estimates were: group 1 (n = 283): 2.2% versus 1.3%, P = .40; group 2 (n = 237): 3.8% versus 3.5%, P = .80; group 3 (n = 111): 6.7% versus 3.2%, P = .05; and group 4 (n = 33): 12.5% versus 8.7%, P = .50. CONCLUSION IBTR! version 2.0 is accurate in the majority of patients with a low to moderate risk of in-breast recurrence. The nomogram still overestimates risk in a minority of patients with higher risk features. Validation in a larger prospective data set is warranted.

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.

The association between biological subtype and isolated regional nodal failure after breast-conserving therapy.

PURPOSE To evaluate the risk of isolated regional nodal failure (RNF) among women with invasive breast cancer treated with breast-conserving surgery (BCS) and radiation therapy (RT) and to determine factors, including biological subtype, associated with RNF. METHODS AND MATERIALS We retrospectively studied 1,000 consecutive women with invasive breast cancer who received breast-conserving surgery and RT from 1997 through 2002. Ninety percent of patients received adjuvant systemic therapy; none received trastuzumab. Sentinel lymph node biopsy was done in 617 patients (62%). Of patients with one to three positive nodes, 34% received regional nodal irradiation (RNI). Biological subtype classification into luminal A, luminal B, HER-2, and basal subtypes was based on estrogen receptor status-, progesterone receptor status-, and HER-2-status of the primary tumor. RESULTS Median follow-up was 77 months. Isolated RNF occurred in 6 patients (0.6%). On univariate analysis, biological subtype (p = 0.0002), lymph node involvement (p = 0.008), lymphovascular invasion (p = 0.02), and Grade 3 histology (p = 0.01) were associated with significantly higher RNF rates. Compared with luminal A, the HER-2 (p = 0.01) and basal (p = 0.08) subtypes were associated with higher RNF rates. The 5-year RNF rate among patients with one to three positive nodes treated with tangents alone was 2.4%; we could not identify a subset of these patients with a substantial risk of RNF. CONCLUSIONS Isolated RNF is a rare occurrence after breast-conserving therapy. Patients with the HER-2 (not treated with trastuzumab) and basal subtypes appear to be at higher risk of developing RNF although this risk is not high enough to justify the addition of RNI. Low rates of RNF in patients with one to three positive nodes suggest that tangential RT without RNI is reasonable in most patients.

Is Biological Subtype Prognostic of Locoregional Recurrence Risk in Women With pT1-2N0 Breast Cancer Treated With Mastectomy?

PURPOSE To examine locoregional and distant recurrence (LRR and DR) in women with pT1-2N0 breast cancer according to approximated subtype and clinicopathologic characteristics. METHODS AND MATERIALS Two independent datasets were pooled and analyzed. The study participants were 1994 patients with pT1-2N0M0 breast cancer, treated with mastectomy without radiation therapy. The patients were classified into 1 of 5 subtypes: luminal A (ER+ or PR+/HER 2-/grade 1-2, n=1202); luminal B (ER+ or PR+/HER 2-/grade 3, n=294); luminal HER 2 (ER+ or PR+/HER 2+, n=221); HER 2 (ER-/PR-/HER 2+, n=105) and triple-negative breast cancer (TNBC) (ER-/PR-/HER 2-, n=172). RESULTS The median follow-up time was 4.3 years. The 5-year Kaplan-Meier (KM) LRR were 1.8% in luminal A, 3.1% in luminal B, 1.7% in luminal HER 2, 1.9% in HER 2, and 1.9% in TNBC cohorts (P=.81). The 5-year KM DR was highest among women with TNBC: 1.8% in luminal A, 5.0% in luminal B, 2.4% in luminal HER 2, 1.1% in HER 2, and 9.6% in TNBC cohorts (P<.001). Among 172 women with TNBC, the 5-year KM LRR were 1.3% with clear margins versus 12.5% with close or positive margins (P=.04). On multivariable analysis, factors that conferred higher LRR risk were tumors>2 cm, lobular histology, and close/positive surgical margins. CONCLUSIONS The 5-year risk of LRR in our pT1-2N0 cohort treated with mastectomy was generally low, with no significant differences observed between approximated subtypes. Among the subtypes, TNBC conferred the highest risk of DR and an elevated risk of LRR in the presence of positive or close margins. Our data suggest that although subtype alone cannot be used as the sole criterion to offer postmastectomy radiation therapy, it may reasonably be considered in conjunction with other clinicopathologic factors including tumor size, histology, and margin status. Larger cohorts and longer follow-up times are needed to define which women with node-negative disease have high postmastectomy LRR risks in contemporary practice.

Clinical outcome of breast cancer occurring after treatment for Hodgkin's lymphoma: case-control analysis

BackgroundTo evaluate diagnosis, management and outcome of breast cancer (BC) occurring after irradiation for Hodgkins lymphoma (HL).Methods39 cases of BC in 28 HL survivors were retrospectively reviewed. 21 patients were included in a case-control analysis.ResultsThe median age at diagnosis of HL and BC was 25.3 and 45.3 years, respectively. The median interval to develop BC was 16.1 years. Eleven women (39.2%) had bilateral disease. Mode of detection of the index breast cancers was by mammographic screening in 17 patients (60.7%), palpable lump in 8 patients (28.6%), clinical examination in two patients (7.1%), and unknown in one patient (3.6%). Case-control analysis showed that histological features and prognosis of BC after HL were similar to those of primary BC, however, for BC after HL, mastectomy was the predominant surgery (P = .001) and adjuvant radiotherapy and anthracycline-based chemotherapy were less frequently used as compared to primary BC (P < .001 and .003, respectively).ConclusionThe previous history of HL does not appear to be a poor prognostic factor for BC occurring thereafter.

Outcome Following Local‐Regional Recurrence in Women with Early‐Stage Breast Cancer: Impact of Biologic Subtype

Local‐regional recurrence (LRR) after breast‐conserving therapy (BCT) can result in distant metastasis and decreased disease‐free survival (DFS). This study examines factors associated with DFS following LRR. The initial population included 2,233 consecutive women who underwent BCT from 1998 to 2007. Biologic subtype was approximated using a combination of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and tumor grade. Cumulative incidence of DFS after LRR was calculated. The association of clinical, pathologic, and treatment parameters with DFS was evaluated using a Cox regression model. At a median follow‐up of 105 months, 82 patients (3.7%) had a LRR. Of these, 66 (80%) were in‐breast and 16 (20%) involved the ipsilateral lymph nodes. Twenty patients subsequently developed distant metastases. Five‐year DFS after initial recurrence was 69.6% for the overall cohort. On univariate analysis, triple‐negative disease (ER/PR/HER2 negative, TNBC) was associated with reduced DFS (HR = 3.8; 95% CI: 1.8–8.1; p < 0.001). Other factors associated with reduced DFS were larger tumor size (HR = 1.3; 95% CI: 1.03–1.6; p = 0.02), shorter interval from initial diagnosis to LRR (HR = 0.98 per month; 95% CI: 0.97–0.99; p = 0.02), and no salvage surgery (HR = 0.2; 95% CI: 0.09–0.5; p = 0.001). On multivariate analysis, TNBC remained the most significant factor associated with reduced DFS (HR = 4.8; 95% CI: 2.25–10.4; p < 0.001). Compared to women with luminal A disease, those with TNBC had significantly worse DFS (37.5% versus 88.3% at 5 years; p < 0.001). Women with TNBC who developed LRR were at high risk of subsequent recurrence. Efforts should be targeted toward both preventing initial recurrence and decreasing subsequent metastasis.

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.