Biomedical subjects
Publications and source records attributed to Thomas A Buchholz.
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The COMMA-Dbeta-geo cell line has been shown to contain a permanent subpopulation of progenitor cells that are enriched in outgrowth potential. Using the COMMA-Dbeta-geo cell line as a model, we sought to study the radioresistance of mammary progenitor cells. Using the putative progenitor cell marker stem cell antigen 1 (Sca1), we were able to isolate a discrete subpopulation of Sca1(+) multipotent cells from the immortalized COMMA-Dbeta-geo murine mammary cell line. At a clinically relevant dose, the Sca1(+) cells were resistant to radiation (2 Gy). Sca1(+) cells contained fewer gamma-H2AX(+) DNA damage foci following irradiation, displayed higher levels of endogenous beta-catenin, and selectively upregulated survivin after radiation. Expression of active beta-catenin enhanced self-renewal preferentially in the Sca1(+) cells, whereas suppressing beta-catenin with a dominant negative, beta-engrailed, decreased self-renewal of the Sca1(+) cells. Understanding the radioresistance of progenitor cells may be an important factor in improving the treatment of cancer. The COMMA-Dbeta-geo cell line may provide a useful model to study the signaling pathways that control mammary progenitor cell regulation.
Recent studies have identified a subpopulation of highly tumorigenic cells with stem/progenitor cell properties from human breast cancers, and it has been suggested that stem/progenitor cells, which remain after breast cancer therapy, may give rise to recurrent disease. We hypothesized that progenitor cells are resistant to radiation, a component of conventional breast cancer therapy, and that that resistance is mediated at least in part by Wnt signaling, which has been implicated in stem cell survival. To test this hypothesis, we investigated radioresistance by treating primary BALB/c mouse mammary epithelial cells with clinically relevant doses of radiation and found enrichment in normal progenitor cells (stem cell antigen 1-positive and side population progenitors). Radiation selectively enriched for progenitors in mammary epithelial cells isolated from transgenic mice with activated Wnt/beta-catenin signaling but not for background-matched controls, and irradiated stem cell antigen 1-positive cells had a selective increase in active beta-catenin and survivin expression compared with stem cell antigen 1-negative cells. In clonogenic assays, colony formation in the stem cell antigen 1-positive progenitors was unaffected by clinically relevant doses of radiation. Radiation also induced enrichment of side population progenitors in the human breast cancer cell line MCF-7. These data demonstrate that, compared with differentiated cells, progenitor cells have different cell survival properties that may facilitate the development of targeted antiprogenitor cell therapies.
PURPOSE: Findings from our previously published phase III randomized trial showed a high pathologic complete remission (CR) rate in patients with human epidermal growth factor receptor 2-positive breast cancer after the concurrent administration of trastuzumab and paclitaxel, followed by concurrent trastuzumab and 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) preoperative chemotherapy. The safety and efficacy data of initial population were updated, with inclusion of additional experience with the same therapy. STUDY DESIGN: The initial randomized study population of 42 patients were randomly assigned to either four cycles of paclitaxel followed by four cycles of FEC or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. All data were updated through November 2005. RESULTS: Pretreatment characteristics of the initial patients and of the second cohort were similar. In the second cohort, pathologic CR rate was 54.5% (95% confidence interval, 32.2-75.6%) and the pathologic CR rate among all patients treated with chemotherapy plus trastuzumab was 60% (95% confidence interval, 44.3-74.3%). Three patients in the chemotherapy only group have recurred, and one has died. There has been no recurrences in the patients randomized to chemotherapy plus trastuzumab, and the estimated disease-free survival at 1 and 3 years was 100% (P = 0.041). In additional cohort treated with chemotherapy and trastuzumab at the median follow-up of 16.3 months, no patients had recurred. No new safety concerns were observed in this study. CONCLUSION: Our expanded cardiac safety data and the updated efficacy data showed that the natural history of this subset of breast cancer patients can be substantially modified by this treatment approach.
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PURPOSE: Static multileaf collimated field-in-field forward-planned intensity-modulated radiation treatment (FiF-IMRT) has been shown to improve dose homogeneity compared to conventional wedged fields. However, a direct comparison of the scattered dose to the contralateral breast resulting from wedged and FiF-IMRT plans remains to be documented. METHODS: The contralateral scattered breast dose was measured in a custom-designed anthropomorphic breast phantom in which 108 thermoluminescent dosimeters (TLDs) were volumetrically placed every 1-2cm. The target phantom breast was treated to a dose of 50Gy using three dose compensation techniques: No medial wedge and a 30-degree lateral wedge (M0-L30), 15-degree lateral and medial wedges (M15-L15), and FiF-IMRT. TLD measurements were compared using analysis of variance. RESULTS: For FiF-IMRT, the mean doses to the medial and lateral quadrants of the contralateral breast were 112cGy (range 65-226cGy) and 40cGy (range 18-91 cGy), respectively. The contralateral breast doses with FiF-IMRT were on average 65% and 82% of the doses obtained with the M15-L15 and M0-L30 techniques, respectively (p<0.001). Compared to the M15-L15 technique, the maximum dose reduction obtained with FiF-IMRT was 115cGy (range 13-115cGy). CONCLUSIONS: The dose to the contralateral breast is significantly reduced with FiF-IMRT compared to wedge-compensated techniques. Although long-term follow-up is needed to establish the clinical relevance of this finding, these results, along with the previously reported improvement in ipsilateral dose homogeneity, support the use of FiF-IMRT if resources permit.
BACKGROUND: African-American (AA) race has been associated with a worse outcome in breast cancer. It is unclear whether this is due to biological factors, socioeconomic factors, or both. METHODS: The records from 2 independent cohorts of breast cancer patients treated on institutional protocols with mastectomy and adjuvant (n = 1456) or neoadjuvant (n = 684) doxorubicin-based chemotherapy were retrospectively reviewed. RESULTS: The adjuvant (Adj) chemotherapy cohort included 1142 Caucasian (CA), 186 Hispanic (HI), and 128 (AA) patients. The neoadjuvant (Neo) chemotherapy protocols included 448 CA, 114 HI, and 122 AA patients. In both groups, AA patients had later-stage tumors (Adj P = .017; Neo P = .051), a higher rate of estrogen receptor (ER)-negative disease (Adj P = .054; Neo P = .039), and a worse 10-year actuarial overall survival rate than CA or HI patients (Adj, 52%, 62%, and 62%, respectively, P = .009; Neo, 40%, 50%, and 56%, respectively, P = .015). In multivariate analyses, AA race remained independently associated with a poorer overall survival rate in both cohorts (Adj, hazard ratio = 1.39, P = .018; Neo, hazard ratio = 1.37, P = .02). CONCLUSIONS: The data suggest that AA race is associated with less favorable biological tumor features, such as an increased likelihood of ER-negative disease, than those found in CA and HI patients. Such differences in tumor biology, as well as previously described socioeconomic factors, likely contribute to the lower rate of survival in the AA breast cancer population.
PURPOSE: The purpose was to assess whether patients with clinical multifocal or multicentric (MFMC) breast cancer determined by mammogram, ultrasound, or physical examination have inferior outcome compared with patients with clinical unicentric lesions. PATIENTS AND METHODS: We retrospectively analyzed 706 consecutive patients with stages I-III breast cancer treated at the M.D. Anderson Cancer Center (Houston, TX) from 1976 to 2003 who received neoadjuvant anthracycline-based chemotherapy followed by breast conservation therapy (BCT), mastectomy alone, or mastectomy plus postmastectomy radiation therapy. RESULTS: The mean follow-up was 66 months. At presentation, 97 of 706 patients had clinically MFMC disease (13.7%). The 5-year rate of locoregional failure was 10% for unicentric disease compared with 7% for MFMC disease (P = .78). Subset analyses of patients by treatment groups confirmed no statistical difference in locoregional control regardless of the type of locoregional treatment. Among patients with multifocal disease treated with BCT, there were no in-breast recurrences and one supraclavicular recurrence. Five-year disease-free survival and overall survival was equivalent between patients with MFMC and unicentric breast cancers. CONCLUSION: Patients with clinical MFMC breast cancer at the time of diagnosis treated with neoadjuvant chemotherapy followed by locoregional therapy have similar 5-year rates of locoregional control, disease-free survival, and overall survival as those with unicentric disease. Clinically detected MFMC disease did not predict for inferior outcome.
BACKGROUND: For women with ductal carcinoma in situ (DCIS), radiation therapy after conservative surgery lowers the risk of recurrence. However, emerging evidence suggests that radiation therapy confers only a marginal absolute benefit for older women with DCIS. In a cohort of older women with DCIS, we sought to determine whether radiation therapy was associated with a clinically significant benefit. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database from January 1, 1992, through December 31, 1999, we identified 3409 women aged 66 years or older treated with conservative surgery for DCIS. A proportional hazards model tested whether radiation therapy was associated with a lower risk of a combined outcome, defined as a subsequent ipsilateral in situ or invasive breast cancer reported by SEER and/or a subsequent mastectomy reported by Medicare claims. The 5-year event risk was determined for patients without and with high-risk features, which were defined as at least one of the following: age 66-69 years, tumor larger than 2.5 cm, comedo histology, and/or high grade. All statistical tests were two-sided. RESULTS: Radiation therapy was associated with a lower risk for each component of the combined outcome (hazard ratio = 0.32, 95% confidence interval [CI] = 0.24 to 0.44). For high-risk patients, the 5-year event risk was 13.6% without radiation therapy versus 3.8% with radiation therapy (difference = 9.8%, 95% CI = 6.5 to 13.2; P<.001). For low-risk patients, the 5-year event risk was 8.2% without radiation therapy versus 1.0% with radiation therapy (difference = 7.2%, 95% CI = 3.6 to 10.9; P<.001). Among healthy women aged 66-79 years, the number needed to treat with radiation therapy to prevent one event in 5 years was 11 for high-risk patients and 15-16 for low-risk patients. CONCLUSION: For older women with DCIS, radiation therapy appears to confer a substantial benefit that remains meaningful even among low-risk patients.
PURPOSE: We previously developed a prognostic index that stratified patients treated with breast conservation therapy (BCT) after neoadjuvant chemotherapy into groups with different risks for local-regional recurrence (LRR). The purpose of this study was to compare the rates of LRR as a function of prognostic index score for patients treated with BCT or mastectomy plus radiation after neoadjuvant chemotherapy. METHODS: We retrospectively analyzed 815 patients treated with neoadjuvant chemotherapy, surgery, and radiation. Patients were assigned an index score from 0 to 4 and given 1 point for the presence of each factor: clinical N2 to N3 disease, lymphovascular invasion, pathologic size>2 cm, and multifocal residual disease. RESULTS: The 10-year LRR rates were very low and similar between the mastectomy and BCT groups for patients with an index score of 0 or 1. For patients with a score of 2, LRR trended lower for those treated with mastectomy vs. BCT (12% vs. 28%, p=0.28). For patients with a score of 3 to 4, LRR was significantly lower for those treated with mastectomy vs. BCT (19% vs. 61%, p=0.009). CONCLUSIONS: This analysis suggests that BCT can provide excellent local-regional treatment for the vast majority of patients after neoadjuvant chemotherapy. For the few patients with a score of 3 to 4, LRR was >60% after BCT and was <20% with mastectomy. If these findings are confirmed in larger randomized studies, the prognostic index may be useful in helping to select the type of surgical treatment for patients treated with neoadjuvant chemotherapy, surgery, and radiation.
PURPOSE: To assess the need for adjuvant radiotherapy following mastectomy for patients with node-negative breast tumors 5 cm or larger. METHODS AND MATERIALS: Between 1981 and 2002, a total of 70 patients with node-negative breast cancer and tumors 5 cm or larger were treated with mastectomy and adjuvant systemic therapies but without radiotherapy at three institutions. We retrospectively assessed rates and risk factors for locoregional failure (LRF), overall survival (OS), and disease-free survival (DFS) in these patients. RESULTS: With a median follow-up of 85 months, the 5-year actuarial LRF rate was 7.6% (95% confidence interval, 3%-16%). LRF was primarily in the chest wall (4/5 local failures), and lymphatic-vascular invasion (LVI) was statistically significantly associated with LRF risk by the log-rank test (p=0.017) and in Cox proportional hazards analysis (p=0.038). The 5-year OS and DFS rates were 83% and 86% respectively. LVI was also significantly associated with OS and DFS in both univariate and multivariate analysis. CONCLUSIONS: This series demonstrates a low LRF rate of 7.6% among breast cancer patients with node-negative tumors 5 cm and larger after mastectomy and adjuvant systemic therapy. Our data indicate that further adjuvant radiation therapy to increase local control may not be indicated by tumor size alone in the absence of positive lymph nodes. LVI was significantly associated with LRF in our series, indicating that patients with this risk factor require careful consideration with regard to further local therapy.
BACKGROUND: Modern radiation techniques, which limit the radiation dose to the heart during treatment for breast cancer, have greatly reduced the risk of radiation-induced cardiac injury. However, the risk of radiation damage to the carotid artery, which is often incidentally included in the supraclavicular radiation field for breast cancer treatment, is not routinely examined, and the technique used to treat this field has not changed significantly from early radiation trials. The purpose of the current study was to compare the incidence of hospitalization for stroke among women with breast cancer treated with supraclavicular radiation with those who received radiation therapy to the breast but not the supraclavicular fossa. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database for 5752 women who were diagnosed with American Joint Committee on Cancer (AJCC) Stage I-III nonmetastatic breast cancer between 1988 and 1997 were analyzed. Women included were age > or = 66 years, had known lymph node (LN) status, had tumors measuring < or = 5 cm, underwent breast surgery, and received adjuvant radiation therapy (with or without supraclavicular irradiation). Patients with < 5 years of follow-up were excluded because events in the first 5 years after radiation were unlikely to be radiation induced. A Cox proportional hazards model was used to compare patients with 0 positive LNs (surrogate group for no supraclavicular radiation, n = 5281) with patients with > 4 positive LNs (surrogate for supraclavicular radiation group, n = 471) for the endpoint of hospitalization for stroke. Time-to-event curves were calculated using the conditional Kaplan-Meier method. RESULTS: The median follow-up for the 0 and 4+ LN cohorts were 92 months and 90 months, respectively (minimum of 60 months). The 10-year and 15-year actuarial freedom from hospitalization for stroke was 91% (0 LN) versus 89.5% (4+ LN) and 79% (0 LN) versus 81.6% (4+ LN), respectively (P = .28). Estrogen receptor status was balanced between the 2 cohorts. As expected, the 4+ cohort had more advanced tumors, higher stage, larger tumor size, and higher grade (P < .0001). In multivariate analysis including LN group, year of diagnosis, age, race, type of surgery, stage, tumor size, grade, estrogen receptor status, and Charlson comorbidity score, only increased age (hazard ratio [HR] for ages 70-74 years, 1.6; HR for ages 75-79 years, 2.1; and HR for age 80 + years, 2.7) and increasing comorbidity score were predictive of an increased risk of hospitalization for stroke. CONCLUSIONS: Although patients with nonbreast malignancies treated with higher doses to the carotid arteries have been shown to have an increased risk of carotid injury, no evidence was found that radiation to the carotid delivered during supraclavicular irradiation for breast cancer increases the risk of hospitalization for stroke.
PURPOSE: To quantify the impact of immediate breast reconstruction on postmastectomy radiation therapy (PMRT) planning. METHODS: A total of 110 patients (112 treatment plans) who had mastectomy with immediate reconstruction followed by radiotherapy were compared with contemporaneous stage-matched patients who had undergone mastectomy without intervening reconstruction. A scoring system was used to assess optimal radiotherapy planning using four parameters: breadth of chest wall coverage, treatment of the ipsilateral internal mammary chain, minimization of lung, and avoidance of heart. An "optimal" plan achieved all objectives or a minor 0.5 point deduction; "moderately" compromised treatment plans had 1.0 or 1.5 point deductions; and "major" compromised plans had > or =2.0 point deductions. RESULTS: Of the 112 PMRT plans scored after reconstruction, 52% had compromises compared with 7% of matched controls (p < 0.0001). Of the compromised plans after reconstruction, 33% were considered to be moderately compromised plans and 19% were major compromised treatment plans. Optimal chest wall coverage, treatment of the ipsilateral internal mammary chain, lung minimization, and heart avoidance was achieved in 79%, 45%, 84%, and 84% of the plans in the group undergoing immediate reconstruction, compared respectively with 100%, 93%, 97%, and 92% of the plans in the control group (p < 0.0001, p < 0.0001, p = 0.0015, and p = 0.1435). In patients with reconstructions, 67% of the "major" compromised radiotherapy plans were left-sided (p < 0.16). CONCLUSIONS: Radiation treatment planning after immediate breast reconstruction was compromised in more than half of the patients (52%), with the largest compromises observed in those with left-sided cancers. For patients with locally advanced breast cancer, the potential for compromised PMRT planning should be considered when deciding between immediate and delayed reconstruction.
PURPOSE: To analyze the results of a Phase III clinical trial that investigated whether a hyperfractionated radiotherapy (RT) schedule could reduce the risk of locoregional recurrence in patients with locally advanced breast cancer treated with chemotherapy and mastectomy. METHODS AND MATERIALS: Between 1985 and 1989, 200 patients with clinical Stage III noninflammatory breast cancer were enrolled in a prospective study investigating neoadjuvant and adjuvant chemotherapy. Of the 179 patients treated with mastectomy after neoadjuvant chemotherapy, 108 participated in a randomized component of the trial that compared a dose-escalated, hyperfractionated (twice-daily, b.i.d.) chest wall RT schedule (72 Gy in 1.2-Gy b.i.d. fractions) with a once-daily (q.d.) schedule (60 Gy in 2-Gy q.d. fractions). In both arms of the study, the supraclavicular fossa and axillary apex were treated once daily to 50 Gy. The median follow-up period was 15 years. RESULTS: The 15-year actuarial locoregional recurrence rate was 7% for the q.d. arm and 12% for the b.i.d. arm (p=0.36). The rates of severe acute toxicity were similar (4% for q.d. vs. 5% for b.i.d.), but moist desquamation developed in 42% of patients in the b.i.d. arm compared with 28% of the patients in the q.d. arm (p=0.16). The 15-year actuarial rate of severe late RT complications did not differ between the two arms (6% for q.d. vs. 11% for b.i.d., p=0.54). CONCLUSION: Although the sample size of this study was small, we found no evidence that this hyperfractionation schedule of postmastectomy RT offered a clinical advantage. Therefore, we have concluded that it should not be further studied in this cohort of patients.
PURPOSE: The aim of this study was to investigate whether patients <35 years old have similar risk of locoregional recurrence after breast conservation therapy compared with patients 35 to 40 years old. METHODS AND MATERIALS: We retrospectively reviewed records of 196 consecutive patients < or =40 years old who received breast conservation therapy (BCT) from 1987 to 2000 for breast cancer and compared outcomes between patients <35 years old with patients 35 to 40 years old. The majority of patients received neoadjuvant chemotherapy as part of their treatment. Multivariate analysis was performed to assess risk factors for locoregional recurrence. RESULTS: After a median follow-up of 64 months, 22 locoregional recurrences (LRR) were observed. Twenty patients developed locoregional recurrence as their first site of relapse. Two patients had bone-only metastases before their locoregional recurrence. On multivariate analysis, age <35 years was associated with a statistically significant increased risk of locoregional recurrence. The 5-year rate of locoregional control was 87.9% in patients <35 years old compared with 91.7% in patients 35 to 40 years old (p = 0.042). CONCLUSIONS: Our finding supports an increased risk of locoregional recurrence as a function of younger age after breast conservation therapy, even among young patients 40 years old and younger.
BACKGROUND: Lymphoscintigraphy (LSG) can identify lymphatic drainage patterns before sentinel lymph node (SLN) biopsy is performed in patients with early-stage breast cancer, but the importance of extraaxillary SLNs seen on LSG is unknown. We assessed whether drainage patterns seen on LSG were associated with histologic findings in axillary SLNs recovered at SLN biopsy. STUDY DESIGN: From a prospectively maintained database, we identified 1,201 clinically node-negative patients with invasive breast cancer who underwent preoperative LSG and axillary SLN biopsy. Patient and tumor characteristics, LSG results, and final SLN pathology results were examined. RESULTS: LSG showed drainage to internal mammary (IM) nodes in 1.6% of patients, axillary nodes in 68.1%, both IM and axillary nodes in 19.8%, and no drainage in 10.3%. Drainage to IM nodes was observed for tumors in all quadrants of the breast. Patients with IM drainage had a younger median age than patients without IM drainage (51.8 versus 58.3 years, respectively; p < 0.001). The intraoperative axillary SLN identification rate was higher when axillary drainage was observed on LSG than when it was not observed (98.7% versus 93.0%, respectively; p < 0.001), but the LSG drainage pattern was not associated with pathologic status of the SLN or number of metastatic SLNs. At a median followup of 32 months, 4 patients had regional nodal recurrence. CONCLUSIONS: Almost one-fourth of patients had lymphatic drainage to the extraaxillary lymph nodes, particularly the IM nodes, seen on LSG. Extraaxillary drainage seen on LSG did not preclude identification of axillary SLNs at operation. Longterm followup of patients with lymphoscintigraphic evidence of extraaxillary drainage is needed to determine whether regional and systemic recurrence patterns differ in these patients.
PURPOSE: Benchmark data regarding quality measures of breast cancer management are needed. We investigated rates of radiation use after breast conservation therapy (BCT) for patients treated for ductal carcinoma-in-situ (DCIS) or invasive breast cancer at National Comprehensive Cancer Network (NCCN) centers. PATIENTS AND METHODS: We studied 3,333 consecutive patients treated between 1997 and 2002 with BCT for DCIS (n = 587) or for stage I or II breast cancer (n = 2,746) in eight NCCN centers. RESULTS: The overall rate of radiation therapy use was 91%, with a lower frequency of radiation use in DCIS versus invasive breast cancers (82% v 94%; odds ratio [OR] = 0.31; P < .0001). In a multivariable analysis of the patients with DCIS, the only factor significantly associated with lower rates of radiation use was low/intermediate grade (OR = 0.19; P = .0003). For patients with invasive breast cancer, significant factors were presence of comorbidity (OR = 0.53; P = .0005), tubular histology (OR = 0.39; P = .02), type of health insurance (P = .0072), and the NCCN institution (P = .0005). The model also showed lower rates of radiation use in patients with stage II disease who did not receive systemic therapy (OR = 0.01; P = .0001), younger patients who did not receive systemic therapy (P = .003); and older patients with stage I disease (P < .0001). CONCLUSION: Radiation use as a component of BCT was high for patients seen at NCCN centers; however, there was variability in practice patterns noted across institutions. Radiation was most commonly omitted in patients with favorable disease characteristics, patients with comorbidities, and patients who also did not receive guideline-recommended systemic treatment.
BACKGROUND: The purpose of the study was to determine the risk of ipsilateral breast carcinoma recurrence (IBCR) and contralateral breast carcinoma (CBC) development in patients with a concurrent diagnosis of ductal carcinoma in situ (DCIS) with atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma in situ (LCIS). METHODS: Records of all 307 patients with DCIS treated with breast-conserving treatment (BCT) from 1968 to 1998 were analyzed. Initial pathology reports and all slides available were re-reviewed for evidence of ADH, ALH, or LCIS. Actuarial local recurrence rates were calculated. RESULTS: Fifty-five cases of DCIS were associated with ADH, 11 with ALH or LCIS, and 14 with both ADH and ALH or LCIS. Overall, IBCR occurred in 14% and no significant difference in the IBCR rate was identified for patients with proliferative lesions compared with patients without these lesions (P = 0.38). Development of CBC in patients with concurrent DCIS and ADH was 4.4 times (95% confidence interval [CI], 1.44-13.63) that in patients with DCIS alone (P < 0.01). The 15-year cumulative rate of CBC development was 22.7% in patients with ALH or LCIS compared with 6.5% in patients without these lesions (P = 0.30) and 19% in patients with ADH compared with 4.1% in patients with DCIS alone (P < 0.01). CONCLUSION: The risk of CBC development is higher with concurrent ADH than in patients with DCIS alone, and these patients may therefore be appropriate candidates for additional chemoprevention strategies. Concurrent ADH, ALH, or LCIS with DCIS is not a contraindication to BCT.