TRIP12 as a mediator of human papillomavirus/p16-related radiation enhancement effects.

Patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) have better responses to radiotherapy and higher overall survival rates than do patients with HPV-negative HNSCC, but the mechanisms underlying this phenomenon are unknown. p16 is used as a surrogate marker for HPV infection. Our goal was to examine the role of p16 in HPV-related favorable treatment outcomes and to investigate the mechanisms by which p16 may regulate radiosensitivity. HNSCC cells and xenografts (HPV/p16-positive and -negative) were used. p16-overexpressing and small hairpin RNA-knockdown cells were generated, and the effect of p16 on radiosensitivity was determined by clonogenic cell survival and tumor growth delay assays. DNA double-strand breaks (DSBs) were assessed by immunofluorescence analysis of 53BP1 foci; DSB levels were determined by neutral comet assay; western blotting was used to evaluate protein changes; changes in protein half-life were tested with a cycloheximide assay; gene expression was examined by real-time polymerase chain reaction; and data from The Cancer Genome Atlas HNSCC project were analyzed. p16 overexpression led to downregulation of TRIP12, which in turn led to increased RNF168 levels, repressed DNA damage repair (DDR), increased 53BP1 foci and enhanced radioresponsiveness. Inhibition of TRIP12 expression further led to radiosensitization, and overexpression of TRIP12 was associated with poor survival in patients with HPV-positive HNSCC. These findings reveal that p16 participates in radiosensitization through influencing DDR and support the rationale of blocking TRIP12 to improve radiotherapy outcomes.

Accelerated partial-breast irradiation using intensity-modulated proton radiotherapy: do uncertainties outweigh potential benefits?

OBJECTIVE: Passive scattering proton beam (PSPB) radiotherapy for accelerated partial-breast irradiation (APBI) provides superior dosimetry for APBI three-dimensional conformal photon radiotherapy (3DCRT). Here we examine the potential incremental benefit of intensity-modulated proton radiotherapy (IMPT) for APBI and compare its dosimetry with PSPB and 3DCRT. METHODS: Two theoretical IMPT plans, TANGENT_PAIR and TANGENT_ENFACE, were created for 11 patients previously treated with 3DCRT APBI and were compared with PSPB and 3DCRT plans for the same CT data sets. The impact of range, motion and set-up uncertainties as well as scanned spot mismatching between fields of IMPT plans was evaluated. RESULTS: IMPT plans for APBI were significantly better regarding breast skin sparing (p<0.005) and other normal tissue sparing than 3DCRT plans (p<0.01) with comparable target coverage (p=ns). IMPT plans were statistically better than PSPB plans regarding breast skin (p<0.002) and non-target breast (p<0.007) in higher dose regions but worse or comparable in lower dose regions. IMPT plans using TANGENT_ENFACE were superior to that using TANGENT_PAIR in terms of target coverage (p<0.003) and normal tissue sparing (p<0.05) in low-dose regions. IMPT uncertainties were demonstrated for multiple causes. Qualitative comparison of dose-volume histogram confidence intervals for IMPT suggests that numeric gains may be offset by IMPT uncertainties. CONCLUSION: Using current clinical dosimetry, PSPB provides excellent dosimetry compared with 3DCRT with fewer uncertainties compared with IMPT. ADVANCES IN KNOWLEDGE: As currently delivered in the clinic, PSPB planning for APBI provides as good or better dosimetry than IMPT with less uncertainty.

Pathologic complete response to neoadjuvant chemotherapy with trastuzumab predicts for improved survival in women with HER2-overexpressing breast cancer.

BACKGROUND: We sought to determine the prognostic value of pathologic response to neoadjuvant chemotherapy with concurrent trastuzumab. PATIENTS AND METHODS: Two hundred and twenty-nine women with HER2/neu (HER2)-overexpressing breast cancer were treated with neoadjuvant chemotherapy plus trastuzumab between 2001 and 2008. Patients were grouped based on pathologic complete response (pCR, n = 114) or less than pCR (

Multifocality and multicentricity in breast cancer and survival outcomes.

BACKGROUND: The clinicopathological characteristics and the prognostic significance of multifocal (MF) and multicentric (MC) breast cancers are not well established. PATIENTS AND METHODS: MF and MC were defined as more than one lesion in the same quadrant or in separate quadrants, respectively. The Kaplan-Meier product limit was used to calculate recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes. RESULTS: Of 3924 patients, 942 (24%) had MF (n = 695) or MC (n = 247) disease. MF/MC disease was associated with higher T stages (T2: 26% versus 21.6%; T3: 7.4% versus 2.3%, P < 0.001), grade 3 disease (44% versus 38.2%, P < 0.001), lymphovascular invasion (26.2% versus 19.3%, P < 0.001), and lymph node metastases (43.1% versus 27.3%, P < 0.001). MC, but not MF, breast cancers were associated with a worse 5-year RFS (90% versus 95%, P = 0.02) and BCSS (95% versus 97%, P = 0.01). Multivariate analysis shows that MF or MC did not have an independent impact on RFS, BCSS, or OS. CONCLUSIONS: MF/MC breast cancers were associated with poor prognostic factors, but were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T stage.

Identifying factors that impact survival among women with inflammatory breast cancer.

BACKGROUND: The objective of this retrospective study was to determine factors impacting survival among women with inflammatory breast cancer (IBC). METHODS: The Surveillance, Epidemiology and End Results Registry (SEER) was searched to identify women with stage III/IV IBC diagnosed between 2004 and 2007. IBC was identified within SEER as T4d disease as defined by the sixth edition of the American Joint Committee on Cancer. The Kaplan-Meier product-limit method was used to describe inflammatory breast cancer-specific survival (IBCS). Cox models were fitted to assess the multivariable relationship of various patient and tumor characteristics and IBCS. RESULTS: Two thousand three hundred and eighty-four women with stage IIIB/C and IV IBC were identified. Two-year IBCS among women with stage IIIB, IIIC and IV disease was 81%, 67% and 42%, respectively (P < 0.0001). In the multivariable model, patients with stage IIIB disease and those with stage IIIC disease had a 63% [hazard ratio (HR) 0.373, 95% confidence interval (CI) 0.296-0.470, P < 0.001] and 31% (HR 0.691, 95% CI 0.512-0.933, P = 0.016) decreased risk of death from IBC, respectively, compared with women with stage IV disease. Other factors significantly associated with decreased risk of death from IBC included low-grade tumors, being of white/other race, undergoing surgery, receiving radiation therapy and hormone receptor-positive disease. Among women with stage IV disease, those who underwent surgery of their primary had a 51% decreased risk of death compared with those who did not undergo surgery (HR = 0.489, 95% CI 0.339-0.704, P < 0.0001). CONCLUSIONS: Although IBC is an aggressive subtype of locally advanced breast cancer, it is heterogeneous with various factors affecting survival. Furthermore, our results indicate that a subgroup of women with stage IV IBC may benefit from aggressive combined modality management.

Risk factors and incidence of thromboembolic events (TEEs) in older men and women with breast cancer.

BACKGROUND: The purpose of this study is to evaluate the risk factors and the prevalence of thromboembolic events (TEEs) in breast cancer patients. PATIENTS AND METHODS: This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare database. Breast cancer patients diagnosed from 1992 to 2005 ≥66 years old were identified. International Classification of Diseases, Ninth Revision, and Healthcare Common Procedure Coding System codes were used to identify TEEs within 1 year of the breast cancer diagnosis. Analyses were conducted using descriptive statistics and logistic regression. RESULTS: A total of 89 841 patients were included, of them 2658 (2.96%) developed a TEE. In the multivariable analysis, males had higher risk of a TEE than women [odd ratio (OR) = 1.57; confidence interval (CI) 1.10-2.25] and blacks had higher risk than whites (OR = 1.20; CI 1.04-1.40). Compared with stage I patients, patients with stage II, III and IV had 22%, 39% and 98% increase, respectively, in risk. Placement of central catheters (OR = 2.71; CI 2.43-3.02), chemotherapy treatment (OR = 1.66; CI 1.48-1.86) or treatment with erythropoiesis-stimulating agents (ESAs) (OR = 1.33; CI 1.33-1.52) increase the risk. Other significant predictors included comorbidities, age, receptor status, marital status and year of diagnosis. Similar estimates were seen for pulmonary embolism, deep vein thromboembolism and other TEEs. CONCLUSIONS: In total, 2.96% of patients in this cohort developed a TEE within 1 year from breast cancer diagnosis. Stage, gender, race, use of chemotherapy and ESAs, comorbidities, receptor status and catheter placement were associated with the development of TEEs.

International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment.

BACKGROUND: Inflammatory breast cancer (IBC) represents the most aggressive presentation of breast cancer. Women diagnosed with IBC typically have a poorer prognosis compared with those diagnosed with non-IBC tumors. Recommendations and guidelines published to date on the diagnosis, management, and follow-up of women with breast cancer have focused primarily on non-IBC tumors. Establishing a minimum standard for clinical diagnosis and treatment of IBC is needed. METHODS: Recognizing IBC to be a distinct entity, a group of international experts met in December 2008 at the First International Conference on Inflammatory Breast Cancer to develop guidelines for the management of IBC. RESULTS: The panel of leading IBC experts formed a consensus on the minimum requirements to accurately diagnose IBC, supported by pathological confirmation. In addition, the panel emphasized a multimodality approach of systemic chemotherapy, surgery, and radiation therapy. CONCLUSIONS: The goal of these guidelines, based on an expert consensus after careful review of published data, is to help the clinical diagnosis of this rare disease and to standardize management of IBC among treating physicians in both the academic and community settings.

Incidence of and survival following brain metastases among women with inflammatory breast cancer.

BACKGROUND: The purpose of this study was to determine the incidence of and survival following brain metastases among women with inflammatory breast cancer (IBC). PATIENTS AND METHODS: Two hundred and three women with newly diagnosed stage III/IV IBC diagnosed from 2003 to 2008, with known Human epidermal growth factor receptor 2 (HER2) and hormone receptor status, were identified. Cumulative incidence of brain metastases was computed. Survival estimates were computed using the Kaplan-Meier product limit method. Multivariable Cox proportional hazards models were fitted to explore the relationship between breast tumor subtype and time to brain metastases. RESULTS: Median follow-up was 20 months. Thirty-two (15.8%) patients developed brain metastases with a cumulative incidence at 1 and 2 years of 2.7% and 18.7%, respectively. Eleven (5.3%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 1 and 2 years of 1.6% and 5.7%, respectively. Compared with women with triple receptor-negative IBC, those with hormone receptor-positive/HER2-negative disease [hazard ratio (HR) = 0.55, 95% confidence interval (CI) 0.19-1.51, P = 0.24] had a decreased risk of developing brain metastases, and those with HER2-positive disease (HR = 1.02, 95% CI 0.43-2.40, P = 0.97) had an increased risk of developing brain metastases, although these associations were not statistically significant. Median survival following a diagnosis of brain metastases was 6 months. CONCLUSION: Women with newly diagnosed IBC have a high early incidence of brain metastases associated with poor survival and may be an ideal cohort to target for site-specific screening.

Inclusion of taxanes, particularly weekly paclitaxel, in preoperative chemotherapy improves pathologic complete response rate in estrogen receptor-positive breast cancers.

BACKGROUND: We examined if inclusion of a taxane and more prolonged preoperative chemotherapy improves pathologic complete response (pCR) rate in estrogen receptor (ER)-positive breast cancer compared with three to four courses of 5-fluorouracil, doxorubicin, cyclophosphamide (FAC). PATIENTS AND METHODS: Pooled analysis of results from seven consecutive neo-adjuvant chemotherapy trials including 1079 patients was carried out. These studies were conducted at MD Anderson Cancer Center from 1974 to 2001. Four hundred and twenty-six (39.5%) patients received taxane-based neo-adjuvant therapy. pCR rates and survival times were analyzed as a function of chemotherapy regimen and ER status. Multivariate logistic and Cox regression analysis were carried out to identify variables associated with pCR and survival. RESULTS: Patients with ER-negative cancer had higher overall pCR rate than patients with ER-positive tumors (20.1% versus 4.9%, P < 0.001). In ER-negative patients, the pCR rates were 29% and 15% with and without a taxane (P < 0.001). In ER-positive patients, the pCR rates were 8.8% and 2.0% with and without a taxane (P < 0.001). In multivariate analysis, clinical tumor size (P < 0.001), ER-negative status (P < 0.001) and inclusion of a taxane (P = 0.01) were independently associated with pCR. For patients with pCR, survival was similar regardless of ER status or the type of regimen that induced pCR. CONCLUSION: pCR rates increased for patients with both ER-positive and ER-negative tumors as regimens started to include a taxane and became longer. This indicates that a subset of patients with ER-positive breast cancer benefits from more aggressive chemotherapy, similarly to patients with ER-negative tumors.

High-dose chemotherapy and autologous peripheral blood stem cell transplantation for primary breast cancer refractory to neoadjuvant chemotherapy.

The role of high-dose chemotherapy (HDCT) in patients with refractory breast cancer is not well established. Forty-two female patients (median age of 46 years) with breast cancer refractory to neoadjuvant chemotherapy received HDCT (cyclophosphamide, carmustine and thiotepa) supported by an autologous peripheral blood stem cells transplant. Their disease had been refractory (defined as less than partial response) to one (18 patients) or two (24 patients) regimens of neoadjuvant chemotherapy. Twenty-nine patients had surgery before HDCT. The best response after surgery, HDCT, and radiation therapy was assessed 60 days after transplantation. Thirty patients had complete remission, eight had a PR, one had a minor response, and three had progressive disease. In seven of 13 patients whose disease was inoperable before HDCT, it became operable. After a median follow-up of 42 months, 21 patients were alive, and 15 remained disease free. Five-year overall survival (OS) was 57% (CI, 50-64%), and the estimated 5-year progression-free survival was 40% (CI, 32-48%). Both OS and PFS were better in patients whose disease became operable after chemotherapy than in those whose disease remained inoperable. A randomized study is warranted in this patient population.

Biphasic metaplastic sarcomatoid carcinoma of the breast.

BACKGROUND: Breast biphasic metaplastic sarcomatoid carcinoma (MSC) is rare and aggressive. We analyzed 100 patients treated at M. D. Anderson Cancer Center (MDACC) with 213 MSC and 98 carcinosarcoma patients identified through the Surveillance, Epidemiology and End-Results (SEER) database to describe clinical and pathologic characteristics. PATIENTS AND METHODS: We searched the MDACC (1985-2001) and SEER databases (1988-2001) for breast MSC and carcinosarcoma patients. RESULTS: We identified 100 MDACC MSC patients: 66% had node-negative disease and 6% distant metastases at presentation. Median recurrence-free survival (RFS) of 94 patients with stages I-III disease was 74 months (range 3-74), with 52% 5-year RFS [95% confidence interval (CI) 0.42-0.63]. Median overall survival in these patients was not reached, with 64% 5-year survival (95% CI 0.54-0.75). The initial stage of the tumor, but not use of adjuvant chemo- or radiotherapy, had a strong association with outcome. The pathologic complete response rate to neoadjuvant chemotherapy was 10%. Median survival from the time of recurrent disease was 14 months (range 1-55). Tumors were usually hormone receptor- and HER2/neu-negative. SEER data were consistent with MDACC findings. CONCLUSIONS: Breast MSC and carcinosarcoma are aggressive, treatment-refractory tumors with shared clinical features and outcome similar to poorly differentiated receptor-negative adenocarcinomas. New therapeutic agents are needed.

Factors predictive of outcome in patients with breast cancer refractory to neoadjuvant chemotherapy.

PURPOSE: The purpose of this study was to determine the clinical, pathological, and treatment factors that are predictive of local-regional recurrence and overall survival for patients with breast cancer that is refractory to neoadjuvant chemotherapy. PATIENTS AND METHODS: This study analyzed the data of the 177 breast cancer patients treated on our institutional protocols who had less than a partial response to neoadjuvant chemotherapy. The initial clinical stage of disease was II in 27%, III in 69%, and IV (supraclavicular lymph node involvement) in 4%. Surgery was performed in 94% of the patients, and 77% of these patients also received adjuvant chemotherapy. RESULTS: After a median follow-up of 5.2 years, 106 patients experienced disease recurrence, with 98 of these having distant metastases and 45 having local-regional recurrence. The 5- and 10-year overall survivals for the entire group were 56% and 33%, respectively. The factors that were independently associated with a statistically significant poorer overall survival in a Cox regression analysis were pathologically involved lymph nodes after surgery, estrogen receptor-negative disease, and progressive disease during neoadjuvant chemotherapy. The 5-year overall survival for patients with pathologically negative lymph nodes ranged from 84% (estrogen receptor-positive disease) to 75% (estrogen re-ceptor-negative disease), compared with rates for patients with pathologically positive lymph nodes of 66% (estrogen receptor-positive disease) and 40% (estrogen receptor-negative disease). The 5-year survival of patients with progressive disease was only 19%. The 5- and 10-year local-regional recurrence rates for the 177 patients were 27% and 34%, respectively. Significant factors on Cox analysis that predicted for local-regional recurrence were four or more pathologically involved lymph nodes and estrogen receptor-negative disease. For the 105 patients treated with surgery and postoperative radiation therapy, the 10-year local-regional recurrence rates for the subgroups with 0, 1, or 2 of these factors were 12%, 25%, and 44%, respectively. CONCLUSIONS: For patients with a poor response to neoadjuvant chemotherapy, conventional treatments achieve reasonable outcomes in those with lymph node-negative disease or estrogen receptor-positive disease. However, more active systemic and local therapies are needed for patients with estrogen receptor-negative disease and positive lymph nodes and for those with clinical evidence of progressive disease during neoadjuvant chemotherapy.

A custom three-dimensional electron bolus technique for optimization of postmastectomy irradiation.

PURPOSE: Postmastectomy irradiation (PMI) is a technically complex treatment requiring consideration of the primary tumor location, possible risk of internal mammary node involvement, varying chest wall thicknesses secondary to surgical defects or body habitus, and risk of damaging normal underlying structures. In this report, we describe the application of a customized three-dimensional (3D) electron bolus technique for delivering PMI. METHODS AND MATERIALS: A customized electron bolus was designed using a 3D planning system. Computed tomography (CT) images of each patient were obtained in treatment position and the volume to be treated was identified. The distal surface of the wax bolus matched the skin surface, and the proximal surface was designed to conform to the 90% isodose surface to the distal surface of the planning target volume (PTV). Dose was calculated with a pencil-beam algorithm correcting for patient heterogeneity. The bolus was then fabricated from modeling wax using a computer-controlled milling device. To aid in quality assurance, CT images with the bolus in place were generated and the dose distribution was computed using these images. RESULTS: This technique optimized the dose distribution while minimizing irradiation of normal tissues. The use of a single anterior field eliminated field junction sites. Two patients who benefited from this option are described: one with altered chest wall geometry (congenital pectus excavatum), and one with recurrent disease in the medial chest wall and internal mammary chain (IMC) area. CONCLUSION: The use of custom 3D electron bolus for PMI is an effective method for optimizing dose delivery. The radiation dose distribution is highly conformal, dose heterogeneity is reduced compared to standard techniques in certain suboptimal settings, and excellent immediate outcome is obtained.

Relationship of sentinel and axillary level I-II lymph nodes to tangential fields used in breast irradiation.

PURPOSE: To evaluate the volume of nodal irradiation associated with breast-conserving therapy, we defined the anatomic relationship of sentinel lymph nodes and axillary level I and II lymph nodes in patients receiving tangential breast irradiation. METHODS AND MATERIALS: A retrospective analysis of 65 simulation fields in women with breast cancer treated with sentinel lymph node surgery and 39 women in whom radiopaque clips demarcated the extent of axillary lymph node dissection was performed. We measured the relationship of the surgical clips to the anatomic landmarks and calculated the percentage of prescribed dose delivered to the sentinel lymph node region. RESULTS: A cranial field edge 2.0 cm below the humeral head the sentinel lymph node region was included or at the field edge in 95% of the cases and the entire extent of axillary I and II dissection in 43% of the axillary dissection cases. In the remaining 57%, this field border encompassed an average of 80% of cranial/caudal extent of axillary level I and II dissection. In 98.5% of the cases, all sentinel lymph nodes were anterior to the deep field edge and 71% were anterior to the chest wall-interface, whereas 61% of the axillary dissection cohort had extension deep to the chest wall-lung interface. If the deep field edge had been set 2 cm below the chest wall-lung interface, the entire axillary dissection would have been included in 82% of the cases, and the entire sentinel lymph node would have been covered with a 0.5-cm margin. The median dose to the sentinel lymph node region was 98% of the prescribed dose. CONCLUSIONS: By extending the cranial border to 2 cm below the humeral head and 2 cm deep to the chest wall-lung interface, the radiotherapy fields used to treat the breast can include the sentinel lymph node region and most of axillary levels I and II.

Verification of tangential breast treatment dose calculations in a commercial 3D treatment planning system.

The accuracy of the photon convolution/superposition dose algorithm employed in a commercial radiation treatment planning system was evaluated for conditions simulating tangential breast treatment. A breast phantom was fabricated from machineable wax and placed on the chest wall of an anthropomorphic phantom. Radiographic film was used to measure the dose distribution at the axial midplane of the breast phantom. Subsequently, thermoluminescent dosimeters (TLDs) were used to measure the dose at four points within the midplane to validate the accuracy of the film dosimetry. Film measurements were compared with calculations performed using the treatment planning system for four types of treatment: optimized wedged beams at 6 and 18 MV and two-dimensional compensated beams at 6 and 18 MV. Both the film- and TLD-measured doses had a precision of approximately 0.6%. The film-measured doses were approximately 1.5% lower than the TLD-measured doses, ranging from 0-3% at 6 MV and 0.5-1% at 18 MV. Such results placed a high level of confidence in the accuracy and precision of the film data. The measured and calculated doses agreed to within +/-3% for both the film and TLD measurements throughout the midplane exclusive of areas not having charged particle equilibrium. Good agreement was not expected within these regions due to the limitations in both film dosimetry and the dose-calculation algorithm. These results indicated that the treatment planning system calculates doses at the midplane with clinically acceptable accuracy in conditions simulating tangential breast treatment.

Breast conservation therapy as a treatment option for the elderly. The M. D. Anderson experience.

BACKGROUND: Although almost half of all incidents of breast carcinoma occur in women age > or = 65 years, not enough is known about appropriate care for patients in this age group. The objective of the current study was to evaluate the role of breast conservation therapy in the management of breast carcinoma in women age > or = 65 years. METHODS: From 1970 to 1994, 1325 patients with carcinoma of the breast were treated with breast conservation therapy (segmental mastectomy and radiation therapy with or without axillary lymph node dissection) at The University of Texas M. D. Anderson Cancer Center. From this patient group, the authors identified 184 elderly women (> or = 65 years) with Stage 0-III disease at the time of diagnosis. RESULTS: The median patient age was 70 years (range, 65-88 years). The distribution of disease by stage among the women was Stage 0 disease in 12 patients (7%), Stage I disease in 107 patients (58%), Stage II disease in 63 patients (34%), and Stage III disease in 2 patients (1%). Comorbid conditions that may have influenced treatment planning were reported in 91 patients (50%). An axillary lymph node dissection was performed in 135 patients (73%), with positive axillary lymph nodes found in 30 patients (22%). Adjuvant chemotherapy was given to 10 patients (5%), and tamoxifen therapy was given to 63 patients (34%). Complications from treatment were reported in 24 patients (13%). With a median follow-up of 7.3 years (range, 0.25-23.5 years), 9 patients developed locoregional disease recurrence (5%), 10 patients developed contralateral breast carcinoma (5%), and 21 patients developed distant metastasis (11%). At last follow-up, 113 patients (61%) were alive, 15 patients (8%) were dead of disease, and 56 patients (30%) were dead of other causes. The 5-year and 10-year disease specific survival rates were 96% and 91%, respectively. CONCLUSIONS: Breast conservation therapy with segmental mastectomy and postoperative radiation therapy with or without axillary lymph node dissection provides excellent local control and disease free survival in elderly women with breast carcinoma. This treatment should be considered as the standard of care for elderly patients without severe comorbid disease.

The influence of pathologic tumor characteristics on locoregional recurrence rates following mastectomy.

PURPOSE: The objective of this study was to evaluate the influence of pathologic factors other than tumor size and number of involved axillary nodes on the risk of locoregional recurrence (LRR) following mastectomy. PATIENTS AND METHODS: We reviewed the medical records of 1031 patients treated with mastectomy and doxorubicin-based chemotherapy without radiation on 5 prospective clinical trials. Median follow-up was 116 months (range, 6-262 months). RESULTS: Patients with gross multicentric disease were at increased risk of LRR (37% at 10 years). However, patients with multifocal disease and those with microscopic multicentric disease did not experience higher rates of LRR than those with single lesions (17% at 10 years). Patients with lymph-vascular space invasion (LVSI) or involvement of the skin or nipple also experienced high rates of LRR (25%, 32%, and 50%, respectively). The presence of close (<5 mm) or positive margins was associated with an increased risk of LRR (45%). The increased risk of LRR observed for patients with pectoral fascial invasion (33%) was not reduced when negative deep margins were obtained. On multivariate analysis, the presence of 4 or more involved axillary nodes, tumor size of greater than 5 cm, close or positive surgical margins, and gross multicentric disease were found to be independent predictors of LRR (all, p < 0.01). In a separate analysis including only patients with 1-3 involved axillary nodes, microscopic invasion of the skin or nipple, pectoral fascial invasion, and the presence of close or positive margins were significant predictors of LRR. CONCLUSION: In addition to the extent of primary and nodal disease, other factors that predict for high rates of LRR include the presence of LVSI, involvement of the skin, nipple or pectoral fascia, close or positive margins, or gross multicentric disease. These factors predict for high LRR rates regardless of the number of involved axillary nodes.

Feasibility of breast preservation in the treatment of occult primary carcinoma presenting with axillary metastases.

BACKGROUND: The objective of the study was to compare the treatment outcomes in patients with occult primary carcinoma with axillary lymph node metastasis who were treated with mastectomy or with intent to preserve the breast. METHODS: From 1951 to 1998, 479 female patients were registered with axillary lymph node metastasis from an unknown primary. After clinical workup, including mammography, 45 patients retained this diagnosis and received treatment for T0 N1-2 M0 carcinoma of the breast. Clinical and pathological data were collected retrospectively, and survival was calculated from the date of initial diagnosis using the Kaplan-Meier method. Median follow-up time was 7 years. RESULTS: Median age was 54 years (range, 32-79). Clinical nodal status was N1 in 71% and N2 in 29% of the patients. Surgical treatment was mastectomy in 29% and an intent to preserve the breast in 71% of the patients. Locoregional radiotherapy was used in 71% and systemic chemoendocrine therapy was used in 73% of the patients. Of the 13 mastectomy patients, only one had a primary tumor discovered in the specimen. Two patients (4%) were ultimately diagnosed with lung cancer and neuroendocrine tumor. No significant difference was detected between mastectomy and breast preservation in locoregional recurrence (15% versus 13%), distant metastases (31% versus 22%), or 5-year survival (75% vs. 79%). Regardless of surgical therapy, the most important determinant of survival was the number of positive nodes. Five-year overall survival was 87% with 1-3 positive nodes compared with 42% with > or =4 positive nodes (P < .0001). CONCLUSIONS: Occult primary carcinoma with axillary metastases can be treated with preservation of the breast without a negative impact on local control or survival.

Recursive partitioning analysis of locoregional recurrence patterns following mastectomy: implications for adjuvant irradiation.

PURPOSE: Postmastectomy irradiation improves overall survival for breast cancer patients at high risk for locoregional recurrence (LRR). The objective of this study was to use recursive partitioning analysis (RPA) to define patient subgroups at high risk for LRR following mastectomy. PATIENTS AND METHODS: A cohort of 1031 patients treated on prospective trials with mastectomy and doxorubicin-based chemotherapy without irradiation was analyzed. The variables considered in the RPA were tumor size, number of involved nodes, number of nodes examined, and percentage of nodes involved (nodes involved/nodes examined). The endpoint was LRR +/- distant metastasis. Only patients with complete data were analyzed (n = 913). Median follow-up was 8 years (range, 0.7-22 years). RESULTS: Involvement of 20% or more of the lymph nodes examined was the most significant variable predicting LRR. Three risk categories were defined. Patients with 20% or more involved nodes and tumors of 3.5 cm or more were at greatest risk for LRR (41% at 8 years). An intermediate-risk group included patients with 20% or more involved nodes and tumors of less than 3.5 cm as well as those with less than 20% involved nodes and tumor size of 5 cm or greater (18% at 8 years). Patients with less than 20% involved nodes and tumor size of less than 5 cm were at lowest risk for LRR (10% at 8 years). CONCLUSION: Tumor size and extent of nodal involvement play interrelated roles in predicting LRR following mastectomy and systemic therapy. Patients with 20% or greater involved nodes and those with less than 20% nodes and tumors of 5.0 cm or greater are at significant risk of LRR and should be considered for postoperative irradiation.