Chemotherapy port related lymphedema after axillary lymph node dissection.

UNLABELLED: The Mascagni lymphatic pathway comprises superficial channels along the clavicle that drain upper extremity lymph. A 65 year-old woman with recurrent left breast cancer presented with a non-functioning chemotherapy port in the right deltopectoral groove. She had undergone right mastectomy with axillary lymph node dissection (ALND). After port removal and wound closure she developed right upper extremity lymphedema. Patients who have undergone ALND may depend solely on this pathway for upper extremity lymphatic drainage. LEVEL OF EVIDENCE: level V.

MET and ERBB2 are coexpressed in ERBB2+ breast cancer and contribute to innate resistance.

UNLABELLED: Breast cancer displays significant intratumoral heterogeneity, which has been shown to have a substantial impact on both innate and acquired resistance to tyrosine kinase inhibitors. The heterogeneous expression of multiple receptor tyrosine kinases (RTK) in cancers supports tumor signaling robustness and plays a significant role in resistance to targeted inhibition. Recent studies have revealed interactions between the MET receptor and the ERBB receptor family in the therapeutic resistance of several cancers. In this study, the relationship between MET expression/activity and the expression/activity of the ERBB receptor family in human breast cancer was interrogated. Importantly, a significant percentage of ERBB2(+) tumors coexpressing MET and ERBB2 were observed and displayed significant heterogeneity with subpopulations of cells that are MET(-)/ERBB2(+), MET(+)/ERBB2(-), and MET(+)/ERBB2(+). In a MET(+)/ERBB2(+) breast cancer cell line, MET depletion resulted in increased ERBB2 activation, and conversely, ERBB2 depletion resulted in increased MET activation. Neither EGFR nor ERBB3 compensated for MET or ERBB2 knockdown. The loss of either MET or ERBB2 led to a decrease in PI3K/AKT signaling and increased dependency on MAPK. These data show that a subset of ERBB2(+) breast cancers express MET and contain MET(+)/ERBB2(+) subpopulations. Moreover, analysis of RTK activation during ERBB2 knockdown indicated that MET signaling is a compensatory pathway of resistance. IMPLICATIONS: ERBB2(+) breast cancers with MET(+)/ERBB2(+) subpopulations may have an innate resistance to ERBB2 inhibition and may benefit from combined MET and ERBB2 inhibition.

Comparison of lymphedema in patients with axillary lymph node dissections to those with sentinel lymph node biopsy followed by immediate and delayed ALND.

PURPOSE: The purpose of the study was to show that delayed axillary lymph node dissection (ALND) has higher rates of lymphedema compared with immediate ALND, using data from NSABP-B32 at Beaumont Hospital. METHOD: NSABP B-32 at Beaumont had 207 patients with follow-up data on 199 patients, randomizing clinically negative axilla to sentinel lymph node biopsy (SLNB)+ALND (GrA N=98), and SLNB+cytology±ALND (GrB N=101). All patients had preoperative volumetric arm measurements and only node negatives had routine postoperative measurements assessing lymphedema for 36 months. We contacted node-positive patients for postoperative measurements for this study. Twenty-four and 15 cytology-positive patients had SLNB+ALND in GrA and GrB, respectively (SubGrA1 N=24; SubGrB1 N=15). Fourteen hematoxylin and eosin-positive patients had delayed ALND (SubGrB2a N=14). RESULTS: Lymphedema rate for node-positive SLNB+ALND was 10.3% [SubGrA1 (3/24)+SubGrB1 (1/15)=4/39] and node-negative SLNB+ALND was 6.8% (SubGrA2=5/74). Lymphedema was 14.3% for delayed ALND in SubGrB2a (2 of 14) and 0% for 72 SLNBs in SubGrB2b. Our study comparing immediate and delayed ALND lymphedema was not statistically significant (10.3% vs. 14.3%, P=0.65). Comparing node-negative ALND (SubGrA2= 5/74=6.8%) to node-positive ALND (A1+B1+B2a=6/53=11.3%) was not statistically significant (P=0.52). Comparing lymphedema for node-negative ALND (SubGrA2) to SLNB (SubGrB2b) only approached significance (6.8% vs. 0%, P=0.058). CONCLUSIONS: The rate of lymphedema was higher in delayed ALND but not statistically significant. Comparison, however, is difficult, given the limited sample size. We urge the other centers of NSABP-B32 to validate this, by contacting the node-positive patients for measurements. The lymphedema rate for SLNB alone was 0% and approached statistical significance when compared with node-negative ALND.

Adoption of gene expression profile testing and association with use of chemotherapy among women with breast cancer.

PURPOSE: Gene expression profile (GEP) testing is a relatively new technology that offers the potential of personalized medicine to patients, yet little is known about its adoption into routine practice. One of the first commercially available GEP tests, a 21-gene profile, was developed to estimate the benefit of adjuvant chemotherapy for hormone receptor-positive breast cancer (HR-positive BC). PATIENTS AND METHODS: By using a prospective registry data set outlining the routine care provided to women diagnosed from 2006 to 2008 with HR-positive BC at 17 comprehensive and community-based cancer centers, we assessed GEP test adoption and the association between testing and chemotherapy use. RESULTS: Of 7,375 women, 20.4% had GEP testing and 50.2% received chemotherapy. Over time, testing increased (14.7% in 2006 to 27.5% in 2008; P < .01) and use of chemotherapy decreased (53.9% in 2006 to 47.0% in 2008; P < .01). Characteristics independently associated with lower odds of testing included African American versus white race (odds ratio [OR], 0.70; 95% CI, 0.54 to 0.92) and high school or less versus more than high school education (OR, 0.63; 95% CI, 0.52 to 0.76). Overall, testing was associated with lower odds of chemotherapy use (OR, 0.70; 95% CI, 0.62 to 0.80). Stratified analyses demonstrated that for small, node-negative cancers, testing was associated with higher odds of chemotherapy use (OR, 11.13; 95% CI, 5.39 to 22.99), whereas for node-positive and large node-negative cancers, testing was associated with lower odds of chemotherapy use (OR, 0.11; 95% CI, 0.07 to 0.17). CONCLUSION: There has been a progressive increase in use of this GEP test and an associated shift in the characteristics of and overall reduction in the proportion of women with HR-positive BC receiving adjuvant chemotherapy.

Improving breast cancer care through a regional quality collaborative.

BACKGROUND: Regional collaborative organizations provide an effective structure for improving the quality of surgical care. With low complication rates and a long latency between surgical care and outcomes such as survival and local recurrence, quality measurement in breast cancer surgery is ideally suited to process measures. Diagnostic biopsy technique for breast cancer diagnosis is measurable and amenable to change at the provider level. We present initial results from our analysis of institutional variation in surgical and core needle biopsy use within a regional breast cancer quality collaborative. METHODS: Established in 2006, the Michigan Breast Oncology Quality Initiative (MiBOQI) consists of 18 hospitals collecting data on breast cancer care using the National Comprehensive Cancer Centers Network (NCCN) Oncology Outcomes Database Project platform to analyze and compare breast cancer practices and outcomes amongst member institutions. Institutional review board approval is obtained at each site. Data are submitted electronically to the NCCN and analyzed for concordance with practice guidelines. Aggregate and blinded data are shared with project directors and institutions at collaborative meetings, and ongoing practice patterns are observed for change. We analyzed variation in breast biopsy technique for initial cancer diagnosis over time and between institutions. Diagnostic biopsies were categorized as core needle, surgical excisional, surgical incisional, and other surgical biopsy. RESULTS: Procedural data for 8,066 patients treated for breast cancer between November 1, 2006 and December 31, 2009 were analyzed. The mean patient age was 59.5 years (range, 25.4-90.0 years). Within MiBOQI, 21% of patients underwent surgical biopsy for initial diagnosis. The percentage of patients undergoing surgical biopsy ranged from 8% to 37%, and the majority of surgical biopsies were classified as excisional biopsies. Patients with ductal carcinoma in situ were more likely to undergo surgical biopsy compared to those with invasive cancer (30.4% vs 17.8%; P < .001). There was no association between biopsy type and patient age, race, or comorbidity. Data on biopsy technique were shared with site project directors and a target surgical biopsy rate of <15% was chosen by consensus. Site project directors disseminated the data to their institutions and developed action plans for provider and patient education. Over the study period, the percentage of cases undergoing surgical biopsy for the entire MiBOQI collaborative decreased from 21% to 15% (P < .001). CONCLUSION: The regional quality collaborative model can be used to collect, analyze, and disseminate surgical breast care quality data to organizations and treating physicians. These data can be used to describe patterns of care and make comparisons over time and between organizations. These data can also be used to set regional quality standards and provide an avenue for physician-led quality improvement.

Long-term cosmetic results and toxicity after accelerated partial-breast irradiation: a method of radiation delivery by interstitial brachytherapy for the treatment of early-stage breast carcinoma.

BACKGROUND: The objective of this study was to assess the cosmesis and toxicities in patients with early-stage breast carcinoma who received treatment with accelerated partial breast irradiation (APBI) using interstitial brachytherapy. METHODS: From April 1993 to December 2001, 199 patients with Stage I-II breast carcinoma received breast-conserving therapy with APBI to the tumor bed alone through a low-dose-rate (LDR) or high-dose-rate (HDR) implant. A template guide was used. The LDR dose was 50 Gray (Gy) over 96 hours; the outpatient HDR implant delivered 32 Gy in 8-Gy or 34 Gy in 10-Gy twice-daily fractions. Cosmesis (Harvard criteria) and toxicities (Radiation Therapy Oncology Group guidelines) were assessed at < or = 6 months, 2 years, and 5 years. RESULTS: The median follow up was 6.4 years. Breast pain, edema, erythema, and hyperpigmentation all diminished over time. Breast fibrosis and hypopigmentation increased until the 2-year mark and then stabilized. Fat necrosis and telangiectasia increased over time, with a fat necrosis rate of 11% at 5 years. Nearly all telangiectasias (34% at 5 yrs) were Grade 1 (< 2 mm). The remaining toxicities were Grade 1 at all follow-up intervals. Infections (11%) occurred predominantly within the first month after treatment. Good-to-excellent cosmetic outcomes were noted in 95-99% of patients over time; cosmetic results stabilized at 2 years with excellent results increased out to 5 years. CONCLUSIONS: APBI with interstitial brachytherapy resulted in mild chronic toxicities, the majority of which diminished or reached a plateau over time. Long-term cosmesis was good to excellent in 95-99% of patients and stabilized at 2 years.

Lymphatic mapping and sentinel node biopsy in women with an ipsilateral second breast carcinoma and a history of breast and axillary surgery.

BACKGROUND: Women with a history of breast and axillary surgery may demonstrate aberrant lymphatic drainage caused by disrupted lymphatic channels. Lymphoscintigraphy may be valuable in evaluation and staging of an ipsilateral second breast carcinoma. METHODS: We conducted a retrospective review of 16 women treated for a second ipsilateral breast carcinoma who underwent breast lymphoscintigraphy and intraoperative lymphatic mapping. Drainage patterns were compared with pathologic and operative findings. RESULTS: Lymphoscintigraphy succeeded in 69% of patients and demonstrated widely varied drainage patterns including ipsilateral axillary and supraclavicular as well as contralateral axillary and supraclavicular basins. No trend between successful lymphatic mapping and multiple clinical and pathologic measures was seen. CONCLUSIONS: In women with a second ipsilateral breast carcinoma and history of previous breast and axillary surgery, lymphoscintigraphy is feasible. Drainage patterns vary widely including across the midline of the thorax. Preoperative lymphoscintigraphy may be useful to ensure inclusion of potential sentinel nodes within the operative field.

Changes in management techniques and patterns of disease recurrence over time in patients with breast carcinoma treated with breast-conserving therapy at a single institution.

BACKGROUND: The authors reviewed changes in the initial clinical presentation, management techniques, and patterns of disease recurrence over time (1981-1996) in patients with breast carcinoma treated with breast-conserving therapy (BCT) at a single institution. The goals of the current study were to determine the frequency and use of optimal local and systemic therapy techniques and to evaluate the impact of these changes on treatment efficacy. METHODS: Six hundred seven patients with American Joint Committee on Cancer Stage I or II invasive breast carcinomas treated with BCT at William Beaumont Hospital (Royal Oak, MI) constituted the study population. All patients received at least an excisional biopsy of the primary tumor, an axillary lymph node staging procedure, and postoperative radiotherapy (RT) (a median tumor bed dose of 61 Gray [Gy] was administered). All sides were reviewed by one pathologist. Numerous clinicopathologic and treatment-related factors were analyzed to monitor changes that occurred over time. Changes in patterns of disease recurrence and treatment efficacy over time also were analyzed. RESULTS: Over the time period analyzed, changes at initial presentation included an increase in the mean age at diagnosis (age 56.1 years vs. 61.4 years; P < 0.001), a decrease in the number of patients with clinically palpable tumors (78% vs. 36%; P < 0.001), a decrease in the mean tumor size (2.2 cm vs. 1.6 cm; P < 0.001), but no change in the percentage of patients with negative lymph nodes (79% vs. 78%; P = 0.83). No differences over time were observed in mean tumor grade (2.0 vs. 1.9; P = 0.2) or the presence of angiolymphatic invasion (27% vs. 26%; P = 0.25). Changes in surgical management and pathologic assessment included the more frequent use of reexcision (46% vs. 81%; P < 0.001), larger mean total volumes of breast tissue specimens excised (115 cm3 vs. 189 cm3; P = 0.001), a larger percentage of patients with final negative surgical margins (74% vs. 97%; P < 0.001), and a small increase in the mean number of lymph nodes excised (13.8 lymph nodes vs. 14.1 lymph nodes; P = 0.01). The only other significant change in the pathologic management of patients over time included a doubling in the mean number of slides examined (10.6 slides vs. 21.1 slides; P < 0.001). Changes in adjuvant local and systemic therapy included an increase in the percentage of patients treated with > 60 Gy to the tumor bed (66% vs. 95%; P < 0.001), a doubling in the mean number of days from the last surgery to the start of RT (24 days vs. 50 days; P < 0.001), and a decrease in the use of regional lymph node RT (24% vs. 8%; P < 0.001). The use of adjuvant tamoxifen increased from 10% to 61% (P < 0.001). Finally, improvements were observed in the 5-year and 12-year actuarial rates of local disease recurrence (8% vs. 1% and 21% vs. 9%, respectively; P = 0.001) and distant metastases (12% vs. 4% and 22% vs. 9%, respectively; P = 0.006). No changes in the mean number of years to ipsilateral (6.5 years vs. 6.4 years; P = 0.59) or distant disease recurrence (4.6 years vs. 3.8 years; P = 0.73) were observed. CONCLUSIONS: The impact of screening mammography and substantial changes in surgical, pathologic, RT, and systemic therapy recommendations were observed over time in the study population. These changes were associated with improvements in 5-year and 12-year local and distant control rates and suggested that improvements in outcome can be realized through adherence to best practice guidelines and continuous monitoring of treatment outcome data.

Ongoing clinical experience utilizing 3D conformal external beam radiotherapy to deliver partial-breast irradiation in patients with early-stage breast cancer treated with breast-conserving therapy.

PURPOSE: We present our ongoing clinical experience utilizing 3D conformal radiation therapy (3D-CRT) to deliver partial-breast irradiation (PBI) in patients with early-stage breast cancer treated with breast-conserving therapy. MATERIALS AND METHODS: Thirty-one patients referred for postoperative radiation therapy after lumpectomy were treated with PBI using our previously reported 3D-CRT technique. Ninety-four percent of patients had surgical clips outlining the lumpectomy cavity (mean: 6 clips). The clinical target volume (CTV) consisted of the lumpectomy cavity plus a 10-mm margin in 9 patients and 15-mm margin in 22 (median: 15 mm). The planning target volume consisted of the CTV plus a 10-mm margin for breathing motion and treatment setup uncertainties. The prescribed dose (PD) was 34 or 38.5 Gy (6 patients and 25 patients, respectively) in 10 fractions b.i.d. separated by 6 h and delivered in 5 consecutive days. Patients were treated in the supine position with 3-5 beams (mean: 4) designed to irradiate the CTV with <10% inhomogeneity and a comparable or lower dose to the heart, lung, and contralateral breast compared with standard whole-breast tangents. The median follow-up duration is 10 months (range: 1-30 months). Four patients have been followed >2 years, 6 >1.5 years, and 5 >1 year. The remaining 16 patients have been followed <12 months. RESULTS: No skin changes greater than Grade 1 erythema were noted during treatment. At the initial 4-8-week follow-up visit, 19 patients (61%) experienced Grade 1 toxicity and 3 patients (10%) Grade 2 toxicity. No Grade 3 toxicities were observed. The remaining 9 patients (29%) had no observable radiation effects. Cosmetic results were rated as good/excellent in all evaluable patients at 6 months (n = 3), 12 months (n = 5), 18 months (n = 6), and in the 4 evaluable patients at >2 years after treatment. The mean coverage of the CTV by the 100% isodose line (IDL) was 98% (range: 54-100%, median: 100%) and by the 95% IDL, 100% (range: 99-100%). The mean coverage of the planning target volume by the 95% IDL was 100% (range: 97-100%). The mean percentage of the breast receiving 100% of the PD was 23% (range: 14-39%). The mean percentage of the breast receiving 50% of the PD was 47% (range: 34-60%). CONCLUSIONS: Utilizing 3D-CRT to deliver PBI is technically feasible, and acute toxicity to date has been minimal. Additional follow-up will be needed to assess the long-term effects of these larger fraction sizes on normal-tissue sequelae and the impact of this fractionation schedule on treatment efficacy.

Estrogen replacement therapy in breast cancer survivors: a matched-controlled series.

OBJECTIVE: We prospectively administered estrogen replacement therapy (ERT) to control estrogen deficiency symptoms in breast cancer survivors as part of our clinical practice. We report the consequences of ERT compared with a historical matched-control group. DESIGN: Two hundred seventy-seven disease-free survivors received ERT. Controls were matched for exact stage, a recurrence-free period similar to the period to ERT initiation in the ERT group, approximate age, and duration of follow-up. The mean time from breast cancer diagnosis to initiation of ERT was 3.61 (+/- 0.25) years, with a median of 1.88 years. The mean duration of ERT was 3.7 (+/- 3.01) years, with a median of 3.05 years. RESULTS: Hot flashes were relieved in 206 of 223 women (92%), dyspareunia/vaginal dryness in 149 of 167 women (89%), and reactive depression/anxiety/mood change in 111 of 126 women (88%). Univariate analysis demonstrated no statistical differences between the groups for age, stage, pathology at diagnosis, progesterone receptor status, local therapy, breast at risk, prior chemotherapy, and duration of follow-up. The ERT group was more likely to be estrogen receptor negative (P = 0.01), to have received prior ERT (P < 0.001), and to have received no adjuvant tamoxifen (P < 0.001). There was no significant difference between the ERT and control groups in ipsilateral primary/recurrence (5/155 v 5/143; P = 0.85), contralateral breast cancers (10/258 v 9/260; P = 0.99), or systemic metastasis (8/277 v 15/277; P = 0.13). Noncause-specific deaths in the control group numbered 15 (of 277), and in the ERT group, 7 (of 277) (P = 0.03). Overall survival favored the ERT group (P = 0.02). CONCLUSIONS: In these selected patients, ERT relieved estrogen deficiency symptoms and did not increase the rate or time to an ipsilateral recurrence/new primary, contralateral new primary, local-regional recurrence, or systemic metastases.