Mei-Ching Liu

Unique features of breast cancer in Taiwan

Between April 1990 and December 1997, 811 consecutive patients with 830 newly diagnosed breast cancers having their primary treatments in our institution were included in this study. Sixty three percent of breast cancer patients were premenopausal. The early-onset breast cancer (age ≤ 40) composed 29.3% of all patients. The five-year survival rate of all patients was 80.4% (95% confidence interval [CI], 76.2–84.6%). The five-year overall survival rate for stage 0 was 95.7% (95% CI, 87.3–100%), stage I, 93.9% (95% CI, 88.9–98.9%), stage II, 88.5% (95% CI, 82.0–95.1%), stage III, 65.0% (95% CI, 54.0–75.9%), and stage IV, 18.5% (95% CI, 3.4–33.7%). Multivariate analysis of primary operable breast cancer revealed that axillary lymph node involvement, high nuclear grade and early-onset breast cancer (age ≤ 40) were poor prognostic factors. The early-onset breast cancer had a more aggressive clinical behavior than that of the older age group, their five-year disease-free survival rates for stage I, stage II and stage III diseases being only 64.7%, 66.5%, and 43.3%, respectively. In these patients the only meaningful prognostic factor was extensive axillary lymph node metastasis (≥10). In summary, breast cancer patients in Taiwan tend to be younger than their counterpart in western countries. The early-onset breast cancer had poorer prognostic features for all stages comparing to the older age group. Standard pathologic factors are not good predictors of their outcome. For these patients new biologic markers need to be sought to distinguish between high and low risk and the treatment strategy for them should be guided by the aggressive characteristics of the disease.

Locoregional failure of postmastectomy patients with 1–3 positive axillary lymph nodes without adjuvant radiotherapy

PURPOSE To analyze the incidence and risk factors for locoregional recurrence (LRR) in patients with breast cancer who had T1 or T2 primary tumor and 1-3 histologically involved axillary lymph nodes treated with modified radical mastectomy without adjuvant radiotherapy (RT). MATERIALS AND METHODS Between April 1991 and December 1998, 125 patients with invasive breast cancer were treated with modified radical mastectomy and were found to have 1-3 positive axillary nodes. The median number of nodes examined was 17 (range 7-33). Of the 125 patients, 110, who had no adjuvant RT and had a minimum follow-up of 25 months, were included in this study. Sixty-nine patients received adjuvant chemotherapy and 84 received adjuvant hormonal therapy with tamoxifen. Patient-related characteristics (age, menopausal status, medial/lateral quadrant of tumor location, T stage, tumor size, estrogen/progesterone receptor protein status, nuclear grade, extracapsular extension, lymphovascular invasion, and number of involved axillary nodes) and treatment-related factors (chemotherapy and hormonal therapy) were analyzed for their impact on LRR. The median follow-up was 54 months. RESULTS Of 110 patients without RT, 17 had LRR during follow-up. The 4-year LRR rate was 16.1% (95% confidence interval [CI] 9.1-23.1%). All but one LRR were isolated LRR without preceding or simultaneous distant metastasis. According to univariate analysis, age <40 years (p = 0.006), T2 classification (p = 0.04), tumor size >==3 cm (p = 0.002), negative estrogen receptor protein status (p = 0.02), presence of lymphovascular invasion (p = 0.02), and no tamoxifen therapy (p = 0.0006) were associated with a significantly higher rate of LRR. Tumor size (p = 0.006) was the only risk factor for LRR with statistical significance in the multivariate analysis. On the basis of the 4 patient-related factors (age <40 years, tumor >==3 cm, negative estrogen receptor protein, and lymphovascular invasion), the high-risk group (with 3 or 4 factors) had a 4-year LRR rate of 66.7% (95% CI 42.8-90.5%) compared with 7.8% (95% CI 2.2-13.3%) for the low-risk group (with 0-2 factors; p = 0.0001). For the 110 patients who received no adjuvant RT, LRR was associated with a 4-year distant metastasis rate of 49.0% (9 of 17, 95% CI 24.6-73.4%). For patients without LRR, it was 13.3% (15 of 93, 95% CI 6.3-20.3%; p = 0.0001). The 4-year survival rate for patients with and without LRR was 75.1% (95% CI 53.8-96.4%) and 88.7% (95% CI 82.1-95.4%; p = 0.049), respectively. LRR was independently associated with a higher risk of distant metastasis and worse survival in multivariate analysis. CONCLUSION LRR after mastectomy is not only a substantial clinical problem, but has a significant impact on the outcome of patients with T1 or T2 primary tumor and 1-3 positive axillary nodes. Patients with risk factors for LRR may need adjuvant RT. Randomized trials are warranted to determine the potential benefit of postmastectomy RT on the survival of patients with a T1 or T2 primary tumor and 1-3 positive nodes.

Adherence to Quality Indicators and Survival in Patients With Breast Cancer

Background:International initiatives increasingly advocate physician adherence to clinical protocols that have been shown to improve outcomes, yet the process-outcome relationship for adhering to breast cancer care protocol is unknown. Objective:This study explores whether 100% adherence to a set of quality indicators applied to individuals with breast cancer is associated with better survival. Research Design and Subjects:Ten quality indicators (4 diagnosis-related and 6 treatment-related indicators) were used to measure the quality of care in 1378 breast cancer patients treated from 1995 to 2001. Adherence to each indicator was based on the number of procedures performed divided by the number of patients eligible for that procedure. The main analysis of adherence was dichotomous (ie, 100% adherence vs. <100% adherence). Measures:The outcome measures studied were 5-year overall survival and progression-free survival, calculated using the Kaplan-Meier method. The Coxs proportional hazard regression model was used for univariate and multivariate analyses. Results:Most patients received care that demonstrated good adherence to the quality indicators. Multivariate analysis revealed that 100% adherence to entire set of quality indicators was significantly associated with better overall survival [hazard ratio (HR): 0.46; 95% confidence interval (CI): 0.33–0.63] and progression-free survival (HR 0.51; 95% CI, 0.39–0.67). One hundred percent adherence to treatment indicators alone was also associated with statistically significant improvements in overall and progression-free survivals. Conclusions:Our study strongly supports that 100% adherence to evidence supported quality-of-care indicators is associated with better survival rates for breast cancer patients and should be a priority for practitioners.

Regulation of CCR5 expression and MIP‐1α production in CD4+ T cells from patients with rheumatoid arthritis

Production of CCR5 expression and MIP‐1α, a ligand of CCR5, by CD4+ T cells from patients with rheumatoid arthritis (RA) were studied. We analysed further the influence of IL‐15 stimulation, CD40/CD40 ligand (CD40L) interaction and CCR5 promotor polymorphism. One hundred and fifty‐five RA patients and another 155 age‐ and sex‐matched healthy individuals were enrolled. Peripheral CD4+ and double negative (DN) T cells from patients had lower portions of CCR5, whereas synovial CD4+ and DN T cells showed a much higher CCR5 expression. IL‐15 significantly up‐regulated the expression of CCR5 on purified CD4+ T cells. CD40L expression on synovial CD4+ T cells was increased greatly in CCR5+ portions by IL‐15. MIP‐1α production by synovial CD4+ T cells was also enhanced by IL‐15. Co‐culture of CD40 expressing synovial fibroblasts with IL‐15‐activated synovial CD4+ T cells significantly increased MIP‐1α production. Expression of CCR5 on patients’ CD4+ T cells was not influenced by the promotor polymorphism of CCR5 gene. Taken together, these data suggest CCR5+CD4+ T cells infiltrate the inflamed synovium and IL‐15 up‐regulates CCR5 and CD40L expression further and enhance MIP‐1α production in synovial CD4+ T cells. Production of MIP‐1α by synovial fibroblasts is significantly increased by engagement of CD40 with CD40L. Synovial microenvironment plays a potential role in regulation of CCR5+CD4+ T cells in rheumatoid joints.

The Benefit and Risk of Postmastectomy Radiation Therapy in Patients with High-risk Breast Cancer

To evaluate the efficacy of postmastectomy radiation therapy (PMRT) for prophylaxis against locoregional recurrence in high-risk breast cancer patients, and the rate of complication associated with such treatment, we retrospectively reviewed 79 breast cancers in 78 patients, who were given therapy (PMRT) between April 1990 and March 1995. Radiation doses were 46-50 Gy in 2-Gy fractions. High-risk factors included primary tumor (> or = 5 cm) in 19 (24.1%) patients, positive axillary lymph nodes (> or = 4) in 56 (70.9%) patients, positive or close (< or = 2 mm) surgical margins in 14 (17.7%) patients, and central or inner quadrant tumor with positive axillary nodes and lymphovascular invasion in seven (8.9%) patients. Adjuvant chemotherapy was also given to 69 of 78 (88.5%), patients and hormonal therapy to 41 of 78 (53.7%) patients. The median follow-up time was 25 months (range, 7-66 months) after mastectomy. Our study revealed that locoregional failure as the first site of failure occurred in only one of 78 (1.3%) patients. Relapse-free survival at 3 years was 67.7% [95% confidence interval (CI), 52.0-81.3], and overall survival was 76.9% (95% CI, 63.3-90.6). The incidence of radiological evidence of lung fibrosis increased significantly in patients whose internal mammary chain was included in the radiation field. The occurrence of lung fibrosis can be reduced by changing radiation treatment technique and keeping central lung distance (CLD) of tangential field to < or = 2.8 cm in tangential field technique or < or = 1.4 cm in tangential with a separate internal mammary field technique. We concluded that the risk of locoregional recurrence in high-risk breast cancer patients can be much reduced by PMRT. With careful selection of radiation treatment fields, radiotherapy technique, and limitation of CLD to < or = 2.8 cm in tangential technique or < or = 1.4 cm in separate technique, the risk of symptomatic radiation pneumonitis is minimal. PMRT should be recommended for breast cancer patients who are at high risk for locoregional recurrence.

Adjuvant sequential chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil (ACMF) with concurrent radiotherapy in resectable advanced breast cancer.

Doxorubicin (Adriamycin) is an anthracycline effective in breast cancer. Despite a worldwide acceptance of Adriamycin in the adjuvant chemotherapy to maximize the survival benefit in the higher risk patients with breast cancer with promising results, oncologists in general do not favorably consider anthracyclines in the adjuvant treatment setting because of concern about the acute and chronic drug-related toxicity. For high-risk patients with breast cancer with more than three positive axillary lymph nodes, this series adopted a modified sequential regimen of ACMF first with Adriamycin (A) as a single agent in 3-weekly administration for three courses, and then a combination of cyclophosphamide, methotrexate, fluorouracil (CMF) every 3 to 4 weeks for six courses given in an outpatient setting concurrent with radiation therapy as an adjuvant treatment. A total of 56 patients underwent modified radical mastectomy and 3 others breast conservation surgery for their invasive breast cancer. Forty-seven (84%) patients completed the intended adjuvant treatment and 1 patient died of infection from treatment-related neutropenia. As a whole, the 3-year overall survival and disease-free survival rates of 56 patients analyzed were 82.3% and 64.4%, respectively. In this high-risk group, patients with four to nine positive nodes showed a slightly better trend of survival than those with 10 or more positive nodes without reaching statistically significant difference (36-month overall survival: 90.9% vs. 72.5%, p = 0.06; disease-free survival: 78.7% vs. 47.8%, p = 0.38). In this entire group of patients, locoregional recurrence was absent. A total of 55 episodes of grade III and IV hematologic toxicity were observed, with only one death from neutropenic sepsis. This modified ACMF regimen offers a good survival rate in breast cancer patients with more than three positive axillary lymph nodes. When these patients are carefully managed, the morbidity and mortality related to the treatment are low.

A General Cutoff Level Combined With Personalized Dynamic Change of Serum Carcinoembryonic Antigen Can Suggest Timely Use of FDG PET for Early Detection of Recurrent Colorectal Cancer.

Purpose FDG PET that has been used is good for diagnosing asymptomatic colorectal cancer (CRC) recurrence in patients with elevated serum carcinoembryonic antigen (CEA) level. However, there is no reference level of CEA rise that would universally suggest the necessity of a PET study. The purpose of this retrospective study was to identify the high-risk group of CRC recurrence through an examination of the dynamics of the CEA level rise as a recurrence indicator. Patients and Methods Between July 2002 and May 2010, 112 patients (59 men, 53 women; age, 18–87 years) had FDG PET for suspicious CRC recurrence indicated by elevated CEA level. We reviewed the PET results and the medical records for recurrence verification and calculated the ratio of increase and the velocity of change in CEA levels for risk stratification. Results The patient-based sensitivity, specificity, and accuracy of PET are 96.6%, 91.3%, and 95.5%, respectively. The probability of recurrence positively correlated with the CEA level rise and the newly diagnosed disease stage. Carcinoembryonic antigen level greater than 13 ng/mL indicated significantly higher risks of recurrence. In patients with CEA level rise of 13 ng/mL or less, an increase over 3.34 times the individualized baseline also indicated high risks of recurrence. Conclusions A posttreatment CEA level rise to greater than 13 ng/mL is suggestive of the optimal use of FDG PET, and so is a mild increase below 13 ng/mL at an increase rate over 3.34.

Neoadjuvant Trastuzumab Concurrent with Nonanthracycline-based Regimens for HER2-positive Locally Advanced Breast Cancer

Trastuzumab, a humanized monoclonal antibody directed against the external domain of the HER-2 protein, has shown remarkable activity against HER-2 positive breast cancer. Consequently, the use of adjuvant trastuzumab plus chemotherapy in patients with HER2-positive stage breast cancer (stage I to III) has become the standard treatment option. However, the role of trastuzumab in neoadjuvant treatment therapy is still uncertain. An increasing number of clinical trials and inadequate analysis show the benefit of adding trastuzumab to chemotherapy in the neoadjuvant setting. We report a case of HER2-positive locally advanced breast cancer in a patient who received cytotoxic agents concomitant with trastuzumab as neoadjuvant therapy, and also review the published literature. The patient achieved pathological complete response, and remained disease-free for more than 5 years.

Late Recurrences in Luminal-Like Breast Cancer

Purpose: The intention of this study is to both examine the disease entity and late recurrences of luminal-like (hormonal receptor positive and HER2-negative) breast cancer, and identify the prognostic factors associated with disease recurrences. Materials and Methods: We selected for this study breast cancer patients initially treated with primary surgeries in our institution between 1990 and 2007, who also fit the following criteria: 1) pathology stage I-III, 2) hormonal receptor-positive, and 3) HER2/neu-negative. Out of the total 1763 eligible patients, 1275 (72%) received adjuvant chemotherapy, 937 (53%) underwent radiotherapy, and 1629 (92%) had hormonal therapy. Cox proportional hazards regression models were used to assess the prognostic significance of the risk factors related to disease recurrences. Results: The five- and ten-year disease-free survival rates were 96% and 91% for stage I patients, 90% and 81% for stage II, and 79% and 65% for stage III patients, respectively. The incidence of recurrence at each stage in the first 5 years was almost equal to that in the second 5 years. The independent risk factors, according to the multivariate analysis, were: age ≤ 40 (hazard ratio [HR] 1.8, 95% confidence interval [CI], 1.4-2.5); tumor ＞ 2cm (HR 1.6, 95% CI, 1.1-2.1); axillary lymph node positive (HR 1.9/2.0/3.9, 95% CI, 1.3-2.8/1.2-3.4/2.2-6.8 for node positive 1-3/4-9/≥10, respectively); nuclear grade III (HR 1.4, 95% CI, 1.1-1.9); the presence of ECS (HR 1.6, 95% CI, 1.1-2.30); and adjuvant hormonal therapy (HR 0.48, 95% CI, 0.30-0.76). Conclusions: Luminal-like (hormonal receptor positive and HER2-negative) breast cancer has excellent long-term outcomes, but also has a considerable frequency of late recurrences. The risk of breast cancer recurrence is relatively high for patients ≤ 40 years of age, with tumor size greater than 2cm, with axillary LN metastasis, status of nuclear grade III, or with ECS involvement. Clinical trials should be considered for these high-risk breast cancer patients, especially for patients who are diagnosed at 40 years of age or younger.

Durable Response to Lapatinib Plus Capecitabine in Trastuzumab-Resistant HER2 Over-expressing Metastatic Breast Cancer

HER2-directed therapy has become an important agent in the treatment of metastatic breast cancer, and has altered the natural course of HER2-overexpressing breast cancer. We report a 54-year-old woman with initial stage breast cancer with subsequent metastasis to the liver, with positive ER and PR, and HER2 over-expression within one year of mastectomy and adjuvant hormone therapy. The patient showed a lengthy positive response, two years in duration, to lapatinib and capecitabine after resistance build-up to traditional chemotherapy and trastuzumab treatment. Here we discuss the effectiveness and mechanisms of the second line anti-HER2 treatment, lapatinib.