Pauline T. Truong

Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer

IntroductionInfiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels.MethodsThe association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1.ResultsIn patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes.ConclusionsER-negative breast cancers with high levels of TIL have heightened sensitivity to anthracycline-based chemotherapy, as assessed by the immediate response to neoadjuvant therapy and long-term outcome following adjuvant therapy. Investigations of TIL-based predictive tests to identify patients likely to benefit from anthracycline-based treatments are warranted.

Interim Cosmetic and Toxicity Results From RAPID: A Randomized Trial of Accelerated Partial Breast Irradiation Using Three-Dimensional Conformal External Beam Radiation Therapy

PURPOSE To report interim cosmetic and toxicity results of a multicenter randomized trial comparing accelerated partial-breast irradiation (APBI) using three-dimensional conformal external beam radiation therapy (3D-CRT) with whole-breast irradiation (WBI). PATIENTS AND METHODS Women age > 40 years with invasive or in situ breast cancer ≤ 3 cm were randomly assigned after breast-conserving surgery to 3D-CRT APBI (38.5 Gy in 10 fractions twice daily) or WBI (42.5 Gy in 16 or 50 Gy in 25 daily fractions ± boost irradiation). The primary outcome was ipsilateral breast tumor recurrence (IBTR). Secondary outcomes were cosmesis and toxicity. Adverse cosmesis was defined as a fair or poor global cosmetic score. After a planned interim cosmetic analysis, the data, safety, and monitoring committee recommended release of results. There have been too few IBTR events to trigger an efficacy analysis. RESULTS Between 2006 and 2011, 2,135 women were randomly assigned to 3D-CRT APBI or WBI. Median follow-up was 36 months. Adverse cosmesis at 3 years was increased among those treated with APBI compared with WBI as assessed by trained nurses (29% v 17%; P < .001), by patients (26% v 18%; P = .0022), and by physicians reviewing digital photographs (35% v 17%; P < .001). Grade 3 toxicities were rare in both treatment arms (1.4% v 0%), but grade 1 and 2 toxicities were increased among those who received APBI compared with WBI (P < .001). CONCLUSION 3D-CRT APBI increased rates of adverse cosmesis and late radiation toxicity compared with standard WBI. Clinicians and patients are cautioned against the use of 3D-CRT APBI outside the context of a controlled trial.

The prognostic significance of the percentage of positive/dissected axillary lymph nodes in breast cancer recurrence and survival in patients with one to three positive axillary lymph nodes

Adjuvant therapy for women with T1–T2 breast carcinoma and 1–3 positive lymph nodes is controversial due to discrepancies in reported baseline locoregional recurrence (LRR) risks. This inconsistency has been attributed to variations in lymph node staging techniques, which have yielded different numbers of dissected lymph nodes. The current study evaluated the prognostic impact of the percentage of positive/dissected lymph nodes on recurrence and survival in women with one to three positive lymph nodes.

DO AGE AND COMORBIDITY IMPACT TREATMENT ALLOCATION AND OUTCOMES IN LIMITED STAGE SMALL-CELL LUNG CANCER? A COMMUNITY-BASED POPULATION ANALYSIS

PURPOSE The effects of age and comorbidity on treatment and outcomes for patients with limited stage small-cell lung cancer (L-SCLC) are unclear. This study analyzes relapse and survival in a community-based population with L-SCLC according to age and comorbidity. METHODS A retrospective review was performed on 174 patients with L-SCLC referred to the British Columbia Cancer Agency, Vancouver Island Centre, between January 1991 and December 1999. Patient and treatment characteristics, disease response, relapse, and survival were compared among three age cohorts: <65 years (n = 55, 32%), 65-74 years (n = 76, 44%), and > or =75 years (n = 43, 25%); and according to Charlson comorbidity scores 0, 1, and > or =2. Multivariate analysis was performed to identify independent prognostic factors associated with treatment response and survival. RESULTS Patient factors that significantly differed with age were functional status classified by Eastern Cooperative Oncology Group performance status and number of comorbidities. Increasing age was significantly associated with fewer diagnostic scans. Combined modality chemoradiotherapy (CRT) was given in 86%, 66%, and 40% of patients ages <65, 65-74, and > or =75 years, respectively, (p <0.0001). Thoracic irradiation use was comparable among the age cohorts (p >0.05), but chemotherapy use varied significantly with less intensive regimens, fewer cycles, and lower total doses with advancing age (p <0.05). Prophylactic cranial irradiation (PCI) was used in 41 patients, only 3 of whom were age >70 years. Overall response rates to primary treatment significantly decreased with advancing age: 91%, 79%, and 74% in patients ages <65, 65-74, and > or =75 years, respectively (p = 0.014). Treatment toxicity and relapse patterns were similar across the age cohorts. Overall 2-year survival rates were significantly lower with advancing age: 37%, 22%, and 19% (p = 0.003), with corresponding median survivals of 17, 12, and 7 months among patients ages <65, 65-74, and > or =75 years, respectively. On multivariate analysis, age and Charlson comorbidity scores were not significantly associated with treatment response and survival. Independent prognostic factors favorably associated with survival were good performance status, normal lactate dehydrogenase, absence of pleural effusion, and > or =four cycles of chemotherapy. CONCLUSION Increasing age was associated with decreased performance status and increased comorbidity. Older patients with L-SCLC were less likely to be treated with CRT, intensive chemotherapy, and PCI. Treatment response and survival rates were lower with advancing age, but this may be attributed to poor performance status and suboptimal treatment rather than age.

Evolving Treatment Strategies for Inflammatory Breast Cancer: A Population-Based Survival Analysis

PURPOSE To determine if mastectomy (Mx) use, chemotherapy (CT) intensity, or treatment sequence of CT, radiation therapy (RT), and Mx have improved outcome for inflammatory breast cancer (IBC). PATIENTS AND METHODS A retrospective analysis of 485 patients with IBC diagnosed in British Columbia between 1980 and 2000 analyzed locoregional relapse-free survival (LRFS) and breast cancer-specific survival (BCSS) by treatment intent and treatment received. Curative intent was defined as delivery of more than four cycles of anthracycline-based CT plus locoregional RT in patients without distant metastases. RESULTS Median follow-up among survivors was 6.5 years. Median BCSS was 1.0 and 3.2 years for patients with distant metastases at diagnosis or those who were curatively treated, respectively. Among patients treated curatively (n = 308), there were no significant differences in LRFS or BCSS with timing of Mx before or after CT/RT, time between diagnosis and RT, or the sequence of RT and CT. Patients receiving more intensive CT had improved 10-year BCSS compared with standard CT (43.7% v 26.3%; P = .04). Ten-year LRFS for patients having Mx after CT, Mx before CT, and without Mx was 62.8%, 58.6%, and 34.4%, respectively (P = .0001); the corresponding 10-year BCSS was 36.9%, 19.9%, and 22.5%, respectively (P = .005). On multivariate analysis, Mx was associated with improved LRFS (P = .04). Independent prognostic factors for BCSS were menopausal status (P = .02), estrogen receptor status (P = .02), and CT type (P = .05). CONCLUSION This retrospective analysis suggested that mastectomy, in conjunction with CT and RT, seemed to enhance locoregional control, whereas modern CT regimens seemed to improve BCSS.

The number of positive nodes and the ratio of positive to excised nodes are significant predictors of survival in women with micrometastatic node-positive breast cancer

BACKGROUND To evaluate the prognostic impact of the number of positive nodes and the lymph node ratio (LNR) of positive to excised nodes on survival in women diagnosed with nodal micrometastatic breast cancer before the era of widespread sentinel lymph node biopsy. METHODS Subjects were 62,551 women identified by the Surveillance Epidemiology and End Results database, diagnosed with pT1-2pN0-1 breast cancer between 1988 and 1997. Kaplan-Meier breast cancer-specific survival (BCSS) and overall survival (OS) were compared between three cohorts: node-negative (pN0, n=57,980) nodal micrometastasis all <or=2mm (pNmic, N=1818), and macroscopic nodal metastasis >2mm but <2 cm (pNmac, n=2753). Nodal subgroups were examined by the number of positive nodes (1-3 versus >or= 4) and the LNR (<or=0.25 versus >0.25). RESULTS Median follow-up was 7.3 yr. Ten-year BCSS and OS in pNmic breast cancer were significantly lower compared to pN0 disease (BCSS 82.3% versus 91.9%, p<0.001 and OS 68.1% versus 75.7%, p<0.001). BCSS and OS with pNmic disease progressively declined with increasing number of positive nodes and increasing LNR. OS with pNmic was similar to pNmac disease when matched by the number of positive nodes and by the LNR. Both pN-based and LNR-based classifications were significantly prognostic of BCSS and OS on Cox regression multivariate analysis. CONCLUSION Nodal micrometastasis is associated with poorer survival compared to pN0 disease. Mortality hazards with nodal micrometastasis increased with increasing number of positive nodes and increasing LNR. The number of positive nodes and the LNR should be considered in risk estimates for patients with nodal micrometastatic breast cancer.

Reliability and validity testing of the Patient and Observer Scar Assessment Scale in evaluating linear scars after breast cancer surgery.

Background: The Patient and Observer Scar Assessment Scale is a promising new method incorporating observer and patient ratings in evaluating burn scars. The authors compared this tool to the Vancouver Scar Scale in a cohort of women with linear scars from breast cancer surgery. Methods: Twenty women with newly diagnosed breast cancer were prospectively accrued. Thirty-one scars were evaluated. The median time from surgery to scar assessment was 8 weeks (range, 3 to 25 weeks). Observer assessment was performed by three independent raters using the Vancouver scale and the observer component of the new tool. Patient self-assessment was performed using the patient component of the tool. Internal consistency, interobserver reliability, and convergent validity were examined. Results: Internal consistency was acceptable for the Vancouver scale and both components of the new tool (Cronbach’s alpha, 0.71, 0.74, and 0.77, respectively). Interobserver reliability was substantial with both the Vancouver scale and the observer tool (average measure intraclass coefficient correlation, 0.78 and 0.60, respectively). The observer tool and Vancouver scale correlated significantly with each other (p < 0.001), but only the observer tool correlated well with patients’ ratings (p = 0.04). Conclusions: In surgical scar assessment, the new Patient and Observer Scar Assessment Scale and Vancouver Scar Scale were both associated with acceptable internal consistency and interobserver reliability. The new tool is more comprehensive and has higher correlation with patients’ ratings. These findings support the use of the new tool as a reliable, valid, and comprehensive approach to assess linear surgical scars.

Patients With T1 to T2 Breast Cancer With One to Three Positive Nodes Have Higher Local and Regional Recurrence Risks Compared With Node-Negative Patients After Breast-Conserving Surgery and Whole-Breast Radiotherapy

PURPOSE To evaluate locoregional recurrence according to nodal status in women with T1 to T2 breast cancer and zero to three positive nodes (0-3N+) treated with breast-conserving surgery (BCS). METHODS AND MATERIALS The study subjects comprised 5,688 women referred to the British Columbia Cancer Agency between 1989 and 1999 with pT1 to T2, 0-3N+, M0 breast cancer, who underwent breast-conserving surgery with clear margins and radiotherapy (RT) of the whole breast. The 10-year Kaplan-Meier local, regional, and locoregional recurrence (LR, RR, and LRR, respectively) were compared between the N0 (n = 4,433) and 1-3N+ (n = 1,255) cohorts. The LRR was also examined in patients with one to three positive nodes (1-3N+) treated with and without nodal RT. Multivariate analysis was performed using Cox regression modeling. RESULTS Median follow-up was 8.6 years. Systemic therapy was used in 97% of 1-3N+ and 41% of N0 patients. Nodal RT was used in 35% of 1-3N+ patients. The 10-year recurrence rates in N0 and 1-3N+ cohorts were as follows: LR 5.1% vs. 5.8% (p = 0.04); RR 2.3% vs. 6.1% (p < 0.001), and LRR 6.7% vs. 10.1% (p < 0.001). Among 817 1-3N+ patients treated without nodal RT, 10-year LRR were 13.8% with age <50 years, 20.3% with Grade III, and 23.4% with estrogen receptor (ER)-negative disease. On multivariate analysis, 1-3N+ status was associated with significantly higher LRR (hazard ratio [HR], 1.85; 95% confidence interval, 1.34-2.55, p < 0.001), whereas nodal RT significantly reduced LRR (HR, 0.59; 95% confidence interval, 0.38-0.92, p = 0.02). CONCLUSION Patients with 1-3N+ and young age, Grade III, or ER-negative disease have high LRR risks approximating 15% to 20% despite BCS, whole-breast RT and systemic therapy. These patients may benefit with more comprehensive RT volume encompassing the regional nodes.

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.

The effects of age and comorbidity on treatment and outcomes in women with endometrial cancer.

Background:Although the incidence of endometrial cancer increases with age, the effect of patient age on treatment selection and outcomes is unclear. In addition, although aging is associated with increased prevalence of comorbid conditions, the extent to which comorbidities influence endometrial cancer management is not well documented. Methods:This population-based analysis evaluates the effect of age and comorbidity on endometrial cancer treatment and outcome in a cohort of 401 patients referred to the Vancouver Island Centre, British Columbia Cancer Agency from 1989 to 1996. Treatment and 5-year actuarial overall survival (OS) and disease-free survival (DFS) were compared by age at diagnosis (<65, 65–74, and ≥75 years) and comorbidity index (Charlson score 0–1 and ≥2). Results:Median follow-up time was 7.8 years. In this cohort, 148 (37%), 152 (38%), and 101 (25%) were aged <65, 65–74, and ≥75 years, respectively. Charlson comorbidity scores ≥2 were found in 18% of patients. Distributions of disease stage, tumor characteristics, and surgical therapy were similar across age and comorbidity subgroups. Standard surgery in this cohort comprised hysterectomy without routine lymphadenectomy. In stage Ic disease, the use of postoperative RT declined with advanced age (96%, 97%, and 74% in patients aged <65, 65–74, and ≥75 years, respectively, P = 0.05) and with increased comorbidities (91% and 79% in patients with Charlson score 0–1 and ≥2, respectively, P = 0.07). Among stage Ic patients aged ≥75 years, pelvic/vaginal relapse occurred in 2 of 6 patients treated with hysterectomy alone compared with 0 of 20 patients treated with postoperative radiotherapy (P = 0.006). On multivariable Cox modeling, age at diagnosis, performance status, stage, grade, lymphovascular invasion, surgery, and radiotherapy use, but not Charlson comorbidity score, were significant predictors for overall survival. Conclusions:Although surgical therapy for endometrial cancer was not influenced by age or comorbidities, reduced use of postoperative radiotherapy in stage Ic disease was observed among women with advanced age and high comorbidity index. The associated pelvic/vaginal relapse rates were higher in elderly patients not treated with radiotherapy. Chronologic age alone should not preclude patients from consideration of optimal local therapy.