Local Therapy For Breast Cancer Research Articles

Percutaneous microwave ablation: a viable local therapy for breast cancer involving the skin/nipple-areola complex?

BackgroundThis study aimed to evaluate the treatment feasibility and efficacy of ultrasound (US)-guided percutaneous microwave ablation (MWA) in patients with breast cancer involving the skin/ nipple-areola complex (NAC). Material and methodsA retrospective study was conducted on 15 patients diagnosed with breast cancer with skin/NAC involvement between December 2017 and April 2023. Throughout hospitalization and subsequent follow-up, regular clinical examinations and comprehensive breast imaging were performed to monitor and assess treatment outcomes. ResultsThe study included fifteen patients diagnosed with breast cancer involving the skin/NAC, with a mean patient age of 60 ± 14 years (range, 33 - 86 years). The mean tumor diameter involving the skin/NAC (n=16) was 5.4 ± 3.1cm (range, 1.0 - 13.0 cm). All patients achieved technique success and technique effectiveness, as confirmed by contrast-enhanced ultrasound combined with dynamic contrast-enhanced magnetic resonance imaging. Before MWA, four patients had breast cancer involving the skin, four had breast cancer involving NAC, and seven had both. Furthermore, five patients presented with skin ulceration/nipple loss. Following MWA, four patients developed both perilesional skin burn and nipple loss, while one patient experienced nipple loss. The median healing time was 3.7 months (range, 2 - 6 months). During a median follow-up of 33.5 months (range, 2 - 63 months), four patients experienced recurrence, and two patients died due to late-phase breast cancer and heart disease, respectively. ConclusionsUS-guided percutaneous MWA shows feasibility and efficacy for managing breast cancer involving the skin/NAC. This technique offers hope for improved therapeutic options and presents a potential alternative treatment approach for these challenging breast cancer patients.

Selenium and dopamine-crosslinked hyaluronic acid hydrogel for chemophotothermal cancer therapy

Sodium selenite (Se)-directed crosslinked hydrogels based on hyaluronic acid (HA)-dopamine (HD), including indocyanine green (ICG), were developed for local therapy of breast cancer. Se can induce polymerization of dopamine (in HD conjugate) by making alkaline pH value, coordinate with the functional groups of HD, and kill cancer cells by pro-oxidant effects. ICG can be entrapped in the crosslinked HD/Se hydrogel network and long lasting photothermal efficacies can be maintained for cancer therapy. HD conjugate was synthesized via an amide linkage between carboxylic acid group of HA and amine group of dopamine. HD/Se gel was fabricated by covalent bonding of dopamine group (in HD conjugate) and the coordination between selenium and functional groups of HD. Controlled rheological properties of HD/Se/ICG gel may provide easy injectability and slow biodegradability. Sufficient photothermal efficiencies were acquired after near-infrared (NIR) laser irradiation. HD/Se/ICG gel structure was remained in the mouse for 2 weeks and severe systemic toxicities were not observed in blood and histological assays. Intratumoral injection of HD/Se/ICG gel with NIR laser irradiation provided the most efficient tumor growth inhibition capability without severe systemic toxicities. HD/Se/ICG hydrogel structure can be introduced as a promising multifunctional platform for local therapy of breast cancers.

Post San Antonio Breast Cancer Symposium 2018

This short review summarizes the most important facts presented at the San Antonio Breast Cancer Symposium 2018 concerning local therapy of breast cancer, including breast and lymph node surgery as well as radiotherapy. Despite the increasing use of neoadjuvant chemotherapy (nCHT) and consequently higher response and pathologic complete response (pCR) rates in the past years, breast-conserving surgery (BCS) has not increased. This is not only due to positive genetic testing, but it is mostly based on patients’ preference. On the other hand, quality of life seems to be better in young patients undergoing BCS regarding satisfaction with breasts and sexual and psychosocial well-being. Thus, surgical decision-making is crucial in young women with breast cancer and long-term quality of life aspects have to be taken into account. The safe performance of sentinel lymph node biopsy in N+ patients with or without neoadjuvant therapy is the current focus of several large randomized controlled trials. In San Antonio, new data about the impact of micro-metastases or extracapsular extension were presented. The 10-year follow-up data from the AMAROS study demonstrated similar axillary recurrence rates in patients with positive sentinel nodes undergoing complete axillary dissection or radiotherapy only. The RAPID study showed that in patients with unifocal small DCIS (Ductal carcinoma in situ) or invasive cancer <3 cm, accelerated partial breast irradiation with three-dimensional conformal radiotherapy was not inferior compared to whole breast irradiation regarding ipsilateral recurrence rate, but the regimen has to be adapted to achieve similar cosmetic results.

Dual thermo-and pH-sensitive injectable hydrogels of chitosan/(poly(N-isopropylacrylamide-co-itaconic acid)) for doxorubicin delivery in breast cancer.

In this work, dual thermo- and pH-responsive hydrogels were developed and loaded with doxorubicin (DOX) with potential therapy of breast cancer. Hydrogels were engineered by blending synthesized poly(N-isopropylacrylamide-co-itaconic acid) (PNIAAm-co-IA) with chitosan (CS) through ionic crosslinking using glycerophosphate (GP). The synthesized copolymer and hydrogels were characterized by means of various techniques such as FT-IR, 1H NMR, scanning electron microscopy (SEM) and energy dispersive X-ray (EDX). Lower critical solution temperature (LCST) of the copolymer was determined around 39 °C using UV-Vis spectroscopy. Swelling studies of hydrogels and their morphology implied the porous structure, high water content with rapid swelling/deswelling rate in response to abrupt changes of pH and temperature. The release investigation of DOX at different concentration, temperature and pH values confirmed the accelerated release of DOX in lower concentration and acidic condition at 37 °C as compared to neutral pH and the temperature of 40 °C. The MTT cytotoxicity study revealed that the hydrogels are cytocompatible and exert no/negligible cytotoxicity on MCF-7 cells. The proliferation of MCF-7 cells on the prepared hydrogel and DOX-loaded hydrogel was evaluated by 4',6-diamidino-2-phenylindole (DAPI) staining which further demonstrated the potential of developed hydrogels for local therapy of breast cancer.

How do Age and Molecular Subtypes Impact Surgical Decisions?

Tumor molecular subtype and patient age are the predominant drivers of recommendations for systemic therapy in patients with breast cancer. Yet, the impact of these factors on surgical decision-making remains controversial. Younger women often receive the most extensive surgical therapy despite a lack of evidence that bigger surgery translates into better outcomes. In contrast, among older women, there is a desire to minimize local therapy and its associated morbidity. Here, we review contemporary data highlighting the relationship between patient age and breast cancer molecular subtype, and local therapy outcomes. Our perspective is that tumor biology, rather than age, should be the driving factor in determining appropriate local therapy for breast cancer.

Abstract BL2: Changing paradigms in the local therapy of breast cancer: Making less more

Abstract The ability of surgery to cure breast cancer has not changed over time. What has changed is that the cancers seen in the screening era are smaller and have fewer nodal metastases, making them more amenable to surgical cure. Only 25% of patients enrolled in the landmark NSABP B-06 trial had cT1N0 disease compared to 80% of those enrolled in NSABP B32, which began 15 years later. At the same time, improved systemic therapy options and a better understanding of tumor biology have led to greater success in treating micrometastatic disease. Systemic therapy is now widespread for early-stage breast cancers and often for longer durations with anti-HER2 therapy given for 12 months and endocrine therapy for 5-10 years. The progressive addition of therapies has increased the burden of treatment for patients at the same time it has improved outcomes. The beneficial effect of systemic therapy on local control and the lower disease burden seen today offer the opportunity to decrease the morbidity of surgery without compromising outcomes. The ACOSOG Z011 trial, now with follow-up of 10 years, demonstrated no difference in locoregional recurrence or survival among patients with metastases in 1–2 sentinel nodes after sentinel node biopsy alone or axillary dissection (ALND) when treated with breast-conserving surgery (BCS) and whole breast irradiation (RT). In 9/2010 we began prospectively utilizing Z11 eligibility criteria in patients with cT1-2 N0 cancers undergoing breast conservation with ALND reserved for those with &amp;gt;2 nodal metastases or gross extracapsular extension. Of the initial 723 consecutive, unselected patients, ALND was avoided in 84%. At a mean follow-up of 33 months (12–68), there were no isolated axillary recurrences. The 5-year Kaplan Meier rate of any nodal recurrence was 98% (95% CI 96–99). In the 251 patients considered “high risk” based on triple negative, HER2+, or age &amp;lt;50 years or a combination of these factors, ALND was required in 15.5% vs 15.9% of postmenopausal, ER+ patients (p=.89). The same principles led us to address the issue of what constitutes an optimal negative margin in women with invasive breast cancer undergoing BCS and RT. After a metaanalysis and review of other relevant literature, an SSO-ASTRO sponsored consensus committee concluded that evidence did not support routinely obtaining margins more widely clear than no ink on tumor, and that adherence to this recommendation, disseminated in late 2013 and published 2/14, had the potential to significantly reduce the use of re-excision. Since that time, the proportion of surgeons in a population-based sample endorsing no ink on tumor as an adequate margin rose to over 60%, compared to 11% in a similar survey conducted in 2006–7. This change in attitude has translated into a reduction in the use of additional surgery, both re-excision and mastectomy after initial lumpectomy. In a SEER sample from 2013–15, this resulted in a 9% absolute increase in the use of BCS during the study period. The use of neoadjuvant therapy offers further opportunities to decrease the morbidity of surgery and individualize local therapy in the future. Citation Format: Morrow M. Changing paradigms in the local therapy of breast cancer: Making less more [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr BL2.

Rethinking the Local Therapy of Breast Cancer: Integration of Biology and Anatomy.

Local control has traditionally been considered a function of disease burden. Local control is now known to differ among biologic subtypes of breast cancer and is greatly improved with the use of systemic therapy. This offers opportunities for decreasing the morbidity of treatment and individualizing local therapy. The use of smaller margins in breast-conserving surgery and elimination of axillary dissection for some node-positive breast cancer patients are current examples of leveraging the benefits of systemic therapy to reduce surgery. Emerging evidence indicates that molecular profiling can identify patients at high and low risk for locoregional recurrence after surgery in a more accurate way than tumor burden, potentially allowing individualization of the use of postmastectomy and comprehensive node field irradiation. Future clinical trials should incorporate both disease burden and molecular profiling when examining treatment strategies.

Is mastectomy undertreatment for low-risk breast cancers eligible for breast-conserving therapy?

Biomarkers are routinely used to predict responses to systemic therapies, but their utility for predicting responses to local therapy for breast cancer is not known. This study determined whether biomarkers could predict responses to breast-conserving therapy (BCT) and mastectomy. A review of the Surveillance, Epidemiology, and End Results database identified women diagnosed with early-stage invasive ductal breast cancer and treated with BCT or mastectomy from 1998 to 2008. The estrogen receptor (ER) status and the histologic grade were used to construct 3 biomarker profiles: low risk (ER-positive, low/intermediate grade), intermediate risk (ER-positive, high grade), and high risk (ER-negative, any grade). The primary measured outcome was disease-specific survival (DSS). BCT and mastectomy were performed in 114,486 patients (59.2%) and 79,035 patients (40.8%), respectively. There were 122,420 low-risk patients (63.3%), 34,341 intermediate-risk patients (17.7%), and 36,760 high-risk patients (19.0%). Multivariate analyses were performed separately for patients with low-, intermediate-, and high-risk tumors. The adjusted hazard ratios for DSS for patients who underwent mastectomy versus BCT for low-, intermediate-, and high-risk tumors were 1.66 (95% confidence interval [CI], 1.54-1.79; P < .001), 1.40 (95% CI, 1.29-1.53; P < .001), and 1.27 (95% CI, 1.19-1.35; P < .001), respectively. Patients with ER-positive, low-grade breast cancers who underwent mastectomy had a 66% increase in disease-specific mortality versus those who underwent BCT. Biomarker profiles defined by the ER status and grade may improve the selection of local therapy for breast cancer.

A historical account of breast cancer surgery: beware of local recurrence but be not radical.

In the late 19th century, William Halsted proposed the radical mastectomy, which became the standard surgical treatment of breast cancer for nearly 100 years. Later in this period, theories suggesting that breast cancer was a systemic disease at inception were championed by Bernard Fisher. This alternative hypothesis of biological predeterminism was based upon results of randomized clinical trials comparing breast conserving therapy with mastectomy, which showed similar overall survival outcomes. Nonetheless, data from meta-analyses suggest that inadequate local therapy can increase risk of local recurrence, which can subsequently increase mortality. In this review, the authors provide an historical account of how local therapy of breast cancer has evolved in the face of improved adjuvant therapies and better understanding of disease biology.

Decision Shared or Otherwise: The Ongoing Evolution of Local Therapy for Breast Cancer

The National Surgical Adjuvant Breast and Bowel Project (NSABP) –B06 trial published over 25 years ago and subsequent trials conclusively showed no difference in survival outcomes between radical mastectomy and breast-conserving surgery (BCS) with radiation. This provided women with breast cancer the option of the less disfiguring, less morbid partial mastectomy. However, over the past 10 years, the proportion of women treated with mastectomy may be increasing despite no scientific data demonstrating its superiority over BCS. Reasons for this trend are unclear but may be related to including increased use of breast MRI, awareness and use of genetic testing, increased patient voice in shared decision and use of mastectomy by high-profile celebrities. In addition there has been an increased-rate prophylactic mastectomy of the unaffected breast. One factor making mastectomy a more palatable option to women and a possible additional driver of increased rates of mastectomy is access to breast reconstruction at the time of or subsequent to mastectomy. In the article accompanying this editorial, Jagsi et al evaluate the rate of reconstruction in women with breast cancer undergoing mastectomy in a modern cohort of privately insured, working-age women. Using MarketScan (Truven Health Analytics, Ann Arbor, MI) a commercial claims-based database, 20,560 women were identified who underwent mastectomy with a breast cancer diagnosis between 1998 and 2007. Among these younger, well-insured women treated with mastectomy, reconstruction increased from 46% in 1998% to 63% in 2007. Reconstruction also correlated with plastic surgeon availability defined by population density of specialists, as well as with geographic region, patient age, and use of bilateral mastectomy. Jagsi et al are to be commended for the highly methodical approach to analyzing these data and for both recognizing and avoiding some of the most dangerous potential biases. However, differences in the cohort over time independent of wider trends in the greater population could have affected the magnitude of the observed change. In 2002, the data set was expanded to include additional health plans, significantly enlarging the cohort available for analysis. The time point of expansion correlates with the increasing reconstruction rates noted in the results. Another factor affecting using these data as indicative of the general population is that this cohort consists mostly of women in noncapitated PPO insurance plans (80%) with over two thirds of patients are within the two highest quartiles in income. Age certainly affects the use of breast reconstruction. Among women over age 65 years (Medicare recipients) reconstruction rates are reported as low as 6% to 16% nationally. In addition, there are personal issues that affect a woman’s choice, and these issues are different for older women. However, there is no evidence demonstrating an increased complication rate in older woman undergoing breast reconstructions, including older women who undergo autologous reconstructions. Older woman should be offered breast reconstruction based on their overall health status and perioperative risk assessment. Treatment also varies by provider. The SEER data cited examining rates of reconstruction in women over 65 reported an average rate of reconstruction for women with Stage 0 to 2 disease of 6%. However, there was significant variability across institutions with reconstruction rates ranging from 0% to 44%, with a few institutions performing a large proportion of the reconstructions. Similarly, patients treated at different National Comprehensive Cancer Network centers nationally were found to have different rates of breast conservation, mastectomy, and mastectomy with reconstruction. This highlights that patient care may be driven by regional culture and provider biases reflected by an institution’s practice, or resource. The type of reconstruction also varies, potentially related to provider bias and interests in the use autologous tissue reconstruction. This occurs most frequently at large or academic centers. While in many cases autologous tissue reconstruction provides superior cosmetic and longer lasting results, autologous reconstructions rates are declining compared with implant reconstruction. Staffing limitations in private practice settings are constrained, often with no trainees or other readily available assistants for the labor-intensive tissue techniques. This trend may also be driven by the low reimbursements rendered for these lengthy and complex procedures. On one survey, many plastic surgeons reported limiting the breast reconstructions performed, citing decrease reimbursement as the reason. Those who continue to perform breast reconstruction are incentivized to perform implant-based reconstruction, with reimbursement as much as six times greater based on intraoperative hourly rates. While physician compensation may be lower, system-wide, autologous tissue reconstruction with either pedicle flaps or free flaps may be more cost effective in the long run than implant-based reconstruction Another key trend is the increased use of contralateral prophylactic mastectomy (CPM) and associated higher rates of implant reconstruction as shown by Jagsi et al. Other studies have duplicated these results with increasing CPM rates and increasing use of implant JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 9 MARCH 2

The Effect of Local Therapy on Breast Cancer Mortality: Is There an Age-Interaction?

There are no randomized trials comparing local therapy versus no therapy in patients with primary breast cancer, as such trials would be deemed unethical. Thus, the impact of local therapy on breast cancer mortality is poorly understood. However, an overview of clinical trials comparing various permutations in the local therapy of breast cancer suggests that inadequate local therapy increases the risk of local recurrences, and thereby increases breast cancer mortality. Yet, age-interactions are commonly reported in studies that have examined the etiology, prognosis, and treatment of breast cancer, and might be associated with the effect of local therapy as well. Moreover, the effect of local therapy on breast cancer mortality might be time-dependent. In cohorts of women with high-risk tumors (predominantly younger women) local therapy may adversely (but only transiently) perturb the natural history of breast cancer. In contrast, such an effect is not evident in cohorts of women with low-risk tumors (predominantly older women). For both groups of patients, local therapy appears to ultimately have a beneficial effect in reducing breast cancer mortality, but in patients with low-risk tumors the benefit is immediate, while in patients with high-risk tumors it is delayed. Evidence for such an age-interaction is derived from comparison of the breast cancer hazard curves in women with high-risk and low-risk tumors, and analysis of the mammography screening trials. Neo-adjuvant systemic therapy may eventually prove useful in modulating the effects of local therapy.

Novel iontophoretic administration method for local therapy of breast cancer

Ductal drug therapy is a novel therapeutic approach for primary breast cancers, particularly those involving ductal carcinoma in situ lesions. Total or partial mastectomy with or without radiotherapy is the standard local therapy for primary breast cancer. Here, we propose a novel drug administration method for ductal drug therapy based on a drug delivery system (DDS) for primary breast cancer. This DDS was designed to deliver miproxifen phosphate (TAT-59), an antiestrogen drug, to ductal lesions via the milk duct, where carcinomas originate, more efficiently than systemic administration, using an iontophoretic technique applied to the nipple (IP administration). Autoradiography imaging confirmed that TAT-59 was directly delivered to the milk duct using IP administration. The plasma concentrations of TAT-59 and its active metabolite DP-TAT-59 were quite low with IP administration. The area under the curve value of DP-TAT-59 in the mammary tissue was approximately 3 times higher with IP administration than with oral administration, at a 6-fold lower dose, indicating higher availability of the drug delivered via DDS than via systemic administration. The low plasma concentrations would limit adverse effects to minor ones. These characteristics show that this DDS is suitable for the delivery of active DP-TAT-59 to ductal lesions.

Long-Term Results of Excision Followed by Radiofrequency Ablation as the Sole Means of Local Therapy for Breast Cancer

Clinical trials have yet to find a size or grade of invasive cancer which can be treated with lumpectomy alone due to the higher local recurrence (LR) rate without radiation (XRT). Excision followed by radiofrequency ablation (eRFA) is an intraoperative method which utilizes heat to create an additional tumor-free zone around the lumpectomy cavity. We hypothesized that eRFA after lumpectomy for invasive breast cancer could reduce the need for re-excision in close margins and potentially maintain local control without the need for XRT. This institutional review board-approved study from July 2002 to December 2010 involved patients undergoing eRFA. A standard lumpectomy was performed and then the RFA probe was deployed 1 cm circumferentially into the walls of the lumpectomy cavity and maintained at 100 °C for 15 min. Validated doppler sonography was used to determine final ablation size. Seventy-three patients (mean age of 68.8 ± 10.9 years) with invasive cancer who had an average tumor size of 1.0 ± 0.54 cm (range of 0.2-2.6 cm) underwent eRFA. Margins were negative in 54, close in 10, focally positive in 6, and grossly positive in 3 patients. Sixteen out of 19 (84 %) of patients with close or positive margins were spared of re-excision. Median follow-up was 55 ± 21 months. Only one patient (1.3 %) developed an in site recurrence. There were three recurrences, elsewhere. Long-term follow-up suggests that eRFA may reduce the need for re- excision as well as reduce LR for invasive breast cancer treated without XRT.

Radiofrequency ablation (RFA) of breast cancer: A multicenter retrospective analysis.

1119 Background: Local ablative therapy of breast cancer represents the next frontier in the minimally invasive breast-conservation treatment. We performed a retrospective study of ultrasound-guided percutaneous radiofrequency ablation (RFA) of breast cancers to determine safety and complication related to this treatment. Methods: Four hundred and ninety-seven patients with core biopsy proven breast carcinoma in 10 institutions of non-surgical ablaton study group underwent RFA without surgical excision were enrolled in this study. Results: Mean patient age was 54 years (range 22 - 92 years). Mean tumor size was 1.6 cm. Four hundred and twenty-five tumors ( 86 %) were ≤ 2 cm. The median follow-up period was 50 months (range 3 – 92 months). The mean required for ablation was 19 minutes (range, 4- 72 minutes), and the average temperature of the tumor after ablation was 91 degrees Celsius. The local recurrence rate after RFA was higher in tumors of negative estrogen receptor (8 of 78, 10%) than in tumors of positive estrogen receptor (17 of 437, 4%; p&lt;0.05), and was higher in tumors of positive HER2/neu than in tumors of negative HER2/neu (14.9% vs. 3.2%; p&lt;0.01). The local recurrence rate after RFA was higher in tumors of positive node than in tumors of negative node (9.8% vs. 3.6%), and was higher in tumors without irradiation than in tumors with irradiation (18.2% vs. 3.2%; p&lt;0.001). The local recurrence rate after RFA was higher in tumors of &gt; 2 cm (13 of 72, 18%) than in tumors of ≤ 2 cm (11 of 425, 3%; p&lt;0.001). RFA-relating adverse events were observed in 17 patients of local pain, 14 patients of skin burn and 4 patients of retraction of nipple. Conclusions: RFA is considered to be a safe and promising minimally invasive treatment of small breast cancer ≤ 2 cm in diameter. Further studies are necessary to optimize the technique and evaluate its future role as local therapy for breast cancer.

Local therapy for breast cancer in malignant lymphoma survivors

Breast cancer is the most frequent secondary tumor in young women previously treated with mantle radiation for Hodgkin's disease. Prior therapeutic radiation to the breast region is considered an absolute contraindication to breast conservative surgery, and mastectomy is considered the treatment of choice. We performed a retrospective review to assess the potential of performing breast conservative surgery and intraoperative radiotherapy with electrons (ELIOT), in these patients. Forty-three patients affected by early breast cancer, previously treated with mantle radiation for malignant lymphoma, who underwent breast conservative surgery and ELIOT, were identified in our institution. Median age at diagnosis of lymphoma was 26 years (49% were less than 25). Median interval between lymphoma and breast cancer occurrence was 19 years. A total dose of 21 Gy (prescribed at 90% isodose) in 39 patients (91%), of 17 Gy (prescribed at 100% isodose) in 1 patient and 18 Gy (prescribed at 90% isodose), was delivered. ELIOT was well tolerated in all patients without any unusual acute or late reactions. After a median follow-up of 52 months, local recurrence occurred in 9% of the patients and metastases in 7% patients. In patients previously treated for lymphoma, partial breast irradiation, and in particular ELIOT, permits breast conservative surgery without acute local complications, decreasing the number of avoidable mastectomies.

S28 Local therapy for breast cancer in malignant lymphoma survivors

S28 Local therapy for breast cancer in malignant lymphoma survivors

Abstract P2-14-02: A Pilot Study of Vascular Endothelial Growth Factor Inhibition with Pazopanib in Patients (pts) with Lymphedema Following Breast Cancer Treatment

Abstract Purpose: Lymphedema is a significant long-term complication of primary therapy for breast cancer. VEGF has a major impact on vascular permeability and lymphangiogenesis. In a prior case control study, we found a significant increase in serum VEGF-C (median 6895 vs. 5349 pg/mL, p=0.0016) in women with lymphedema compared to women without lymphedema suggesting inhibition of VEGF-C as a potential therapeutic strategy. Methods: Pts with significant unilateral lymphedema were treated with pazopanib 800 mg/day continuously. Baseline assessments include arm volume, interstitial fluid pressure (IFP), extracellular fluid volume by lymphometer (ECF), quality of life (QOL) and plasma VEGF-C,-D, and R3. IFP was measured serially for 24 hours after the first treatment; arm volume, ECF, QOL, and plasma VEGF-C/D/R3 are assessed every 4 weeks. Results: Ten pts were enrolled. Median duration of lymphedema was 3.5 years (0.7-8.2) Median time since surgery was 5.1 years (1.0-14.2); median time since radiation (n=9) was 4.7 years (0.4-8.8). Complete IFP data are available in 7 pts. Baseline IFP was significantly higher in the affected compared to unaffected arm (mean 5.73 vs. -1.78 mmHg; p=0.0005). Mean IFP in the affected arm decreased an average of 76% 24 hours after initiation of pazopanib (5.73 vs. 1.56 mmHg; p=0.0061). Toxicity was greater than anticipated with grade 3 fatigue (n=3), arthralgia (n=2), and anorexia (n=1); three pts discontinued therapy prior to the first post-treatment assessment. Five pts met the definition of response with a ≥25% reduction in excess arm volume four weeks after initiating treatment. ECF significantly (p=0.014) decreased as well though the mean difference in excess arm volume did not significantly change (p=0.06). Conclusions: Preliminary data supports the hypothesis that VEGF plays a role in the development and/or persistence of lymphedema after local therapy for breast cancer. Pazopanib acutely decreases IFP, leading to a decrease in ECF and modest improvement in arm volume but results in significant toxicity at the dose used on this study. Subsequent studies will explore a lower dose of pazopanib in this population. This study was supported by the Breast Cancer Research Foundation with pazopanib supplied by GSK. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-02.

A pilot study of vascular endothelial growth factor inhibition with bevacizumab in patients with lymphedema following breast cancer treatment

9523 Background: Lymphedema is a significant long-term complication of primary therapy for breast cancer. Anecdotally, several patients (pts) with metastatic disease treated with bevacizumab monotherapy noted improvement in long-standing lymphedema. This pilot study was conducted to explore these observations prospectively. Methods: We used an existing biospecimen bank to conduct a case-control study to compare VEGF-A, -C, -D and VEGFR-3 serum concentrations in breast cancer pts with and without lymphedema (matched for age and LN status). In a separate pilot trial, pts with significant unilateral lymphedema receive bevacizumab, 15 mg/kg every 3 weeks. Baseline assessments include arm volume, interstitial fluid pressure (IFP), extracellular fluid volume by lymphometer (ECF), quality of life (QOL) and plasma VEGF-C, -D, and R3. IFP is measured serially for 24 hours after the first treatment; arm volume, ECF, QOL, and plasma VEGF-C/D/R3 are assessed at 3 and 6 weeks. Results: Samples were available for 16 pts with chronic lymphedema and 31 matched controls. Median VEGF-C levels were significantly increased in pts with lymphedema (6895 pg/ml vs. 5349 pg/ml, p=0.001). Twelve pts have been enrolled in the pilot trial. Median duration of lymphedema was 6.3 years (0.5–16.6) Median time since surgery was 5.5 years (1.9–17.6); median time since radiation (n=10) was 5.1 years (1.3–8.3). Complete IFP data is available in 9 pts. Baseline IFP was significantly higher in the affected compared to unaffected arm (7.63 vs. -0.87 mmHg; p=0.0023). Mean IFP in the affected arm decreased an average of 41.9% 24 hours after bevacizumab infusion (7.63 vs. 4.88 mmHg; p=0.07). ECF, VEGF-1, and VEGF-R3 levels all significantly decreased three weeks after initial treatment. Two patients met the definition of response with a ≥ 25% reduction in excess arm volume though the mean difference in excess arm volume did not significantly change (p=0.19). Conclusions: Preliminary data supports the hypothesis that VEGF plays a central role in the development and persistence of lymphedema after local therapy for breast cancer. Bevacizumab acutely decreases IFP, leading to a decrease in ECF and modest improvement in arm volume. [Table: see text]

Does it matter where you go for breast cancer surgery?

6504 Background: Variation in receipt of local therapy for breast cancer has motivated research addressing whether treatment differences are attributable to surgeons. We assessed the amount of variation in receipt of mastectomy and breast reconstruction attributable to surgeons and evaluated patient and surgeon factors associated with treatment variability. Methods: Women with non-metastatic breast cancer aged 20–79 diagnosed from June 2005-February 2007 in Detroit and Los Angeles were surveyed after surgical treatment (response rate 72%, N = 2,260). Attending surgeons were surveyed (response rate 76.1%, N = 318). Patient and surgeon data were merged to SEER data (1764 patients and 295 surgeons). Two dependent variables were receipt of mastectomy and reconstruction. Patient variables were age, ethnicity, marital status, tumor size, behavior, and grade. Surgeon factors included age, gender, years in practice, percent of total practice devoted to breast cancer, hospital setting, and 3 scales measuring patient management processes. We used separate random effects models for each dependent variable to determine the amount of treatment variation attributable to surgeons and the amount of within-surgeon variability explained by patient and surgeon factors. Results: The number of patients per surgeon ranged from 1 to 35 (mean 5.5). One-third of women received mastectomy, 30% of whom received reconstruction. The amount of variation in mastectomy attributable to individual surgeons was moderate (8%, median odds ratio 1.7). Patient factors explained half this variation, while surgeon factors explained very little (&lt;1%). The amount of variation in reconstruction attributable to individual surgeons was large (18%, median odds ratio 2.3), with patient level factors explaining one third of this variation. One surgeon level factor (propensity to refer to a plastic surgeon prior to surgery) explained an additional third of the variance. Conclusions: These results suggest that individual surgeons and their attributes contribute only modestly to the variation in primary surgery for breast cancer. By contrast, individual surgeons play a much larger role in explaining the wide variation in receipt of breast reconstruction- primarily through preoperative referral to plastic surgeons. No significant financial relationships to disclose.

A pilot study of vascular endothelial growth factor inhibition with bevacizumab in patients with lymphedema following breast cancer treatment.

Abstract Abstract #6142 Purpose: Lymphedema is a significant long-term complication of primary therapy for breast cancer but little is known regarding its etiology and persistence other than relation to the number of lymph nodes (LN) removed. We suggest the following model: Mechanical disruption of normal lymphatic drainage leads to increased back pressure on lymphatic vessels producing an increase in interstitial fluid pressure (IFP). The increased in IFP triggers local production of VEGF-C to stimulate compensatory lymphangiogenesis. As VEGF-A (and to a lesser extent –C) also increases vascular permeability, the consequent increase in interstitial fluid and edema predominate. Anecdotally, several patients (pts) with metastatic disease treated with bevacizumab monotherapy noted improvement in long-standing lymphedema. This pilot study was conducted to explore these observations prospectively.&amp;#x2028; Methods: We used an existing biospecimen bank to conduct a case-control study to compare VEGF-A, -C, -D and VEGFR-3 serum concentrations in breast cancer pts with and without lymphedema (matched for age and LN status). In a separate pilot trial, pts with significant unilateral lymphedema receive bevacizumab, 15 mg/kg every 3 weeks. Baseline assessments include arm volume, interstitial fluid pressure (IFP), extracellular fluid volume by lymphometer (ECF), quality of life (QOL) and plasma VEGF-C, -D, and R-3. IFP is measured serially for 24 hours after the first treatment; arm volume, ECF, QOL, and plasma VEGF-C/D/R-3 are assessed at 3 and 6 weeks.&amp;#x2028; Results: Samples were available for 16 pts with chronic lymphedema and 24 matched controls. Median VEGF-C levels were significantly increased in pts with lymphedema (6895 pg/ml vs. 5349 pg/ml, p=0.001). Median VEGF-A levels were slightly higher in pts with lymphedema (375 pg/ml vs.250 pg/ml, p=NS). Eight pts have been enrolled in the pilot trial thus far. Median duration of lymphedema was 4.4 years (2.2-16.6) Median time since surgery was 7.1 years (3.4-17.6); median time since radiation (n=7) was 4.4 years (2.3-7.9). Complete IFP data is available in 5 pts. Baseline IFP was significantly higher in the affected compared to unaffected arm (9.04 vs. -2.07 mmHg; p=0.0017). Median IFP in the affected arm decreased an average of 42.6% 24 hours after bevacizumab infusion (11.1 vs. 6.9 mmHg; p=0.09). Total arm circumference decreased by an average of 2.8 cm three weeks after initial treatment.&amp;#x2028; Conclusions: Preliminary data supports the hypothesis that VEGF plays a central role in the development and persistence of lymphedema after local therapy for breast cancer. Inhibiting VEGF acutely decreases IFP and may be an effective treatment. Treatment and accrual to the pilot trial continues; full data will be available by December 2008. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6142.