Mehra Golshan

Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance)

PURPOSE One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab. PATIENTS AND METHODS Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m(2) once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed. RESULTS Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated. CONCLUSION In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.

Internal Mammary Nodes in Breast Cancer: Diagnosis and Implications for Patient Management—A Systematic Review

The management of internal mammary nodes (IMNs) in breast cancer is controversial. Surgical series from the 1950s showed that one third of breast cancer patients had IMN involvement, with a higher risk in patients with medial tumors and/or positive axillary nodes. IMN metastasis has similar prognostic importance as axillary nodal involvement. However, after three randomized trials showed no survival benefit from extended mastectomy compared with radical or modified radical mastectomy, IMN dissection was largely abandoned. Recently, lymphoscintigraphy studies have renewed interest in IMN evaluation. Approximately one fifth of internal mammary sentinel nodes are pathologic, although most centers do not perform IMN biopsies because of concerns about morbidity and lack of established survival benefit. In addition, results from randomized trials testing the value of postmastectomy irradiation and a meta-analysis of 78 randomized trials have provided high levels of evidence that local-regional tumor control is associated with long-term survival improvements. This benefit was limited to trials that used systemic therapy, which was not routinely administered in the earlier surgical studies, although the contribution from IMN treatment is unclear. IMN irradiation has also been shown to cause increased cardiac morbidity. Before mature results from current randomized trials assessing the benefit of IMN irradiation become available, lymphoscintigraphy may be used to help guide decisions regarding systemic and local-regional treatment. However, even in patients with visualized primary IMN drainage, the potential benefit of treatment should be balanced against the risk of added morbidity.

Risk Perceptions and Psychosocial Outcomes of Women With Ductal Carcinoma In Situ: Longitudinal Results From a Cohort Study

BACKGROUND Ductal carcinoma in situ (DCIS) has a generally favorable overall prognosis, with a systemic recurrence rate of approximately 1%, a local recurrence rate after mastectomy of 1%, and a local recurrence rate after breast-conserving treatment of less than 10%. Preliminary studies have suggested that women with DCIS may overestimate their risk of disease recurrence. Few data exist regarding psychosocial outcomes for women with DCIS. METHODS Women in Eastern Massachusetts with newly diagnosed DCIS were asked to participate in a longitudinal study of risk perceptions, psychosocial concerns, and health behaviors. Psychosocial outcomes after DCIS diagnosis and risk perceptions were evaluated at enrollment and at 9 and 18 months. All statistical tests were two-sided. RESULTS Four hundred eighty-seven women with DCIS (64% of eligible participants) completed the enrollment survey. Overall quality of life was good among the women surveyed, and the substantial anxiety at enrollment decreased with time (P < .001). At enrollment, 54% perceived at least a moderate risk for DCIS recurrence in the next 5 years, 68% in their lifetime; 39% perceived at least a moderate risk for invasive cancer in the next 5 years, 53% in their lifetime; and 28% perceived at least a moderate likelihood of DCIS spreading to other places in their body. At 18 months after enrollment, perceived risks had not statistically significantly changed from those at enrollment (P = .38). Anxiety at enrollment was the factor that was most consistently and strongly associated with overestimation of future breast cancer-related risks (perceived moderate or greater risk vs less than moderate risk of DCIS recurring within 5 years: odds ratio [OR] = 4.0, 95% confidence interval [CI] = 1.6 to 9.9, P = .003; of invasive breast cancer within 5 years: OR = 4.3, 95% CI = 1.9 to 9.9, P < .001; and of invasive breast cancer during lifetime: OR = 5.3, 95% CI = 2.0 to 14.3, P < .001). CONCLUSIONS Many women with newly diagnosed DCIS have inaccurate perceptions of the breast cancer risks that they face, and anxiety is particularly associated with these inaccurate perceptions.

Magnetic resonance imaging as a predictor of pathologic response in patients treated with neoadjuvant systemic treatment for operable breast cancer. Translational Breast Cancer Research Consortium trial 017.

Increased pathologic complete response (pCR) rates observed with neoadjuvant chemotherapy (NCT) for some subsets of patients with invasive breast cancer have prompted interest in whether patients who achieved a pCR can be identified preoperatively and potentially spared the morbidity of surgery. The objective of this multicenter, retrospective study was to estimate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting a pCR in the breast.

Matched Pair Analyses of Stage IV Breast Cancer with or Without Resection of Primary Breast Site

BackgroundReports demonstrate improved survival of stage IV breast cancer patients with primary cancer resection. This may result from selection for surgery, rather than biological processes.MethodsWe performed matched-pair analysis that minimized potential bias in selecting surgery for primary cancer. Chart review was also performed of 5-year survivors to assess selection bias affecting breast surgery.Results19,464 breast cancer patients were identified; 808 (4.2%) were stage IV: 622 were analyzed after eliminating wrong diagnoses or staging, and limiting patients to Massachusetts residents.Matched-pair analysis narrowed or eliminated apparent survival benefit associated with primary site surgery in several comparisons. When the impact of the sequence of systemic and surgical treatments was studied in stage IV patients, 90% 2-year survival occurred in patients receiving chemotherapy first, in contrast to receiving chemotherapy simultaneously with or after surgery, suggesting selection for delayed surgery after excellent response to initial chemotherapy. In bone metastases, the 2-year survival advantage occurred with chemotherapy before surgery; no difference in survival with or without surgery occurred when these treatments were simultaneous.Among 5-year survivors, frequency of primary site surgery after excellent response to systemic therapy, breast surgery in stage III patients incorrectly classified as stage IV, and frequency of oligo metastases all indicated selection bias.ConclusionsCase selection bias in primary breast cancer resection in state IV patients may explain most, if not all, the apparent survival advantage of such surgery.

Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis

Significance This study is the first demonstration, to our knowledge, of the application of desorption electrospray ionization mass spectrometry imaging (DESI-MSI) for discrimination of breast cancer and delineation of tumor margins. Using DESI-MSI, it is possible to discriminate between cancerous and adjacent normal tissue on the basis of the detection and specific spatial distributions of different lipid species. This study proves the feasibility of classifying cancerous and normal breast tissues using ambient ionization MSI. It will allow the surgeon to access to this information in real time so as to make accurate intraoperative decisions quickly. It will result in improved cosmesis and decrease the need for multiple operations for margin reexcision. Distinguishing tumor from normal glandular breast tissue is an important step in breast-conserving surgery. Because this distinction can be challenging in the operative setting, up to 40% of patients require an additional operation when traditional approaches are used. Here, we present a proof-of-concept study to determine the feasibility of using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) for identifying and differentiating tumor from normal breast tissue. We show that tumor margins can be identified using the spatial distributions and varying intensities of different lipids. Several fatty acids, including oleic acid, were more abundant in the cancerous tissue than in normal tissues. The cancer margins delineated by the molecular images from DESI-MSI were consistent with those margins obtained from histological staining. Our findings prove the feasibility of classifying cancerous and normal breast tissues using ambient ionization MSI. The results suggest that an MS-based method could be developed for the rapid intraoperative detection of residual cancer tissue during breast-conserving surgery.

Survival Benefit of Breast Surgery for Low-Grade Ductal Carcinoma In Situ: A Population-Based Cohort Study

IMPORTANCE While the prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially following the introduction of breast-screening methods, the clinical significance of early detection and treatment for DCIS remains unclear. OBJECTIVE To investigate the survival benefit of breast surgery for low-grade DCIS. DESIGN, SETTING, AND PARTICIPANTS A retrospective longitudinal cohort study using the Surveillance, Epidemiology, and End Results (SEER) database from October 9, 2014, to January 15, 2015, at the Dana-Farber/Brigham Womens Cancer Center. Between 1988 and 2011, 57,222 eligible cases of DCIS with known nuclear grade and surgery status were identified. EXPOSURES Patients were divided into surgery and nonsurgery groups. MAIN OUTCOMES AND MEASURES Propensity score weighting was used to balance patient backgrounds between groups. A log-rank test and multivariable Cox proportional hazards model was used to assess factors related to overall and breast cancer-specific survival. RESULTS Of 57,222 cases of DCIS identified in this study, 1169 cases (2.0%) were managed without surgery and 56,053 cases (98.0%) were managed with surgery. With a median follow-up of 72 months from diagnosis, there were 576 breast cancer-specific deaths (1.0%). The weighted 10-year breast cancer-specific survival was 93.4% for the nonsurgery group and 98.5% for the surgery group (log-rank test, P < .001). The degree of survival benefit among those managed surgically differed according to nuclear grade (P = .003). For low-grade DCIS, the weighted 10-year breast cancer-specific survival of the nonsurgery group was 98.8% and that of the surgery group was 98.6% (P = .95). Multivariable analysis showed there was no significant difference in the weighted hazard ratios of breast cancer-specific survival between the surgery and nonsurgery groups for low-grade DCIS. The weighted hazard ratios of intermediate- and high-grade DCIS were significantly different (low grade: hazard ratio, 0.85; 95% CI, 0.21-3.52; intermediate grade: hazard ratio, 0.23; 95% CI, 0.14-0.42; and high grade: hazard ratio, 0.15; 95% CI, 0.11-0.23) and similar results were seen for overall survival. CONCLUSIONS AND RELEVANCE The survival benefit of performing breast surgery for low-grade DCIS was lower than that for intermediate- or high-grade DCIS. A prospective clinical trial is warranted to investigate the feasibility of active surveillance for the management of low-grade DCIS.

Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients.

Significance Emerging evidence indicates patients who benefit from antiangiogenic therapies have improved vessel function. To determine how bevacizumab modulates vessel morphology to improve vessel function we conducted a phase II trial of preoperative bevacizumab followed by bevacizumab combined with chemotherapy in HER2-negative breast cancer patients. Our results suggest that the clinical response to bevacizumab may occur through an increase in the extent of vascular normalization primarily in patients with a high baseline tumor microvessel density. If validated, these observations suggest approaches to improve antiangiogenic therapy and to identify patients likely to benefit. Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning.

Growing Use of Contralateral Prophylactic Mastectomy Despite no Improvement in Long-term Survival for Invasive Breast Cancer.

OBJECTIVE To update and examine national temporal trends in contralateral prophylactic mastectomy (CPM) and determine whether survival differed for invasive breast cancer patients based on hormone receptor (HR) status and age. METHODS We identified women diagnosed with unilateral stage I to III breast cancer between 1998 and 2012 within the Surveillance, Epidemiology, and End Results registry. We compared characteristics and temporal trends between patients undergoing breast-conserving surgery, unilateral mastectomy, and CPM. We then performed Cox proportional-hazards regression to examine breast cancer-specific survival (BCSS) and overall survival (OS) in women diagnosed between 1998 and 2007, who underwent breast-conserving surgery with radiation (breast-conserving therapy), unilateral mastectomy, or CPM, with subsequent subgroup analysis stratifying by age and HR status. RESULTS Of 496,488 women diagnosed with unilateral invasive breast cancer, 59.6% underwent breast-conserving surgery, 33.4% underwent unilateral mastectomy, and 7.0% underwent CPM. Overall, the proportion of women undergoing CPM increased from 3.9% in 2002 to 12.7% in 2012 (P < 0.001). Reconstructive surgery was performed in 48.3% of CPM patients compared with only 16.0% of unilateral mastectomy patients, with rates of reconstruction with CPM rising from 35.3% in 2002 to 55.4% in 2012 (P < 0.001). When compared with breast-conserving therapy, we found no significant improvement in BCSS or OS for women undergoing CPM (BCSS: HR 1.08, 95% confidence interval 1.01-1.16; OS: HR 1.08, 95% confidence interval 1.03-1.14), regardless of HR status or age. CONCLUSIONS The use of CPM more than tripled during the study period despite evidence suggesting no survival benefit over breast conservation. Further examination on how to optimally counsel women about surgical options is warranted.Objective: To update and examine national temporal trends in contralateral prophylactic mastectomy (CPM) and determine whether survival differed for invasive breast cancer patients based on hormone receptor (HR) status and age. Methods: We identified women diagnosed with unilateral stage I to III breast cancer between 1998 and 2012 within the Surveillance, Epidemiology, and End Results registry. We compared characteristics and temporal trends between patients undergoing breast-conserving surgery, unilateral mastectomy, and CPM. We then performed Cox proportional-hazards regression to examine breast cancer-specific survival (BCSS) and overall survival (OS) in women diagnosed between 1998 and 2007, who underwent breast-conserving surgery with radiation (breast-conserving therapy), unilateral mastectomy, or CPM, with subsequent subgroup analysis stratifying by age and HR status. Results: Of 496,488 women diagnosed with unilateral invasive breast cancer, 59.6% underwent breast-conserving surgery, 33.4% underwent unilateral mastectomy, and 7.0% underwent CPM. Overall, the proportion of women undergoing CPM increased from 3.9% in 2002 to 12.7% in 2012 (P < 0.001). Reconstructive surgery was performed in 48.3% of CPM patients compared with only 16.0% of unilateral mastectomy patients, with rates of reconstruction with CPM rising from 35.3% in 2002 to 55.4% in 2012 (P < 0.001). When compared with breast-conserving therapy, we found no significant improvement in BCSS or OS for women undergoing CPM (BCSS: HR 1.08, 95% confidence interval 1.01–1.16; OS: HR 1.08, 95% confidence interval 1.03–1.14), regardless of HR status or age. Conclusions: The use of CPM more than tripled during the study period despite evidence suggesting no survival benefit over breast conservation. Further examination on how to optimally counsel women about surgical options is warranted.

Can Methylene Blue Only Be Used in Sentinel Lymph Node Biopsy for Breast Cancer

Abstract:  Sentinel lymph node biopsy (SLNB) has become an accepted standard of care to stage the axilla for clinically node‐negative early stage breast cancer. In experienced hands, studies have shown an acceptable rate of identification of the sentinel lymph node (SLN) with blue dye only. Lymphazurin is occasionally associated with severe allergic reaction, including anaphylaxis and death. The use of methylene blue alone as a method of identifying the SLN in breast cancer has been reported once previously in the literature. Methylene blue may be an acceptable alternative with fewer deleterious side effects. Medical records of patients, who underwent sentinel node mapping between September 2003 and March 2005 by two surgeons at an academic medical center were reviewed. SLN mapping was performed by periareolar injection of 5 cc of 1% methylene blue. All patients with positive SLNs underwent completion axillary node dissection. During the study period, 141 consecutive patients with clinically node‐negative axillas and without evidence of inflammatory breast cancer underwent SLNB with injection of methylene blue only. A SLN was identified in 136 of 141 patients (96.5%). Thirty‐three of 136 SLNs (24%) harbored metastatic disease. No cases of anaphylaxis were noted. In experienced hands, methylene blue alone is a highly sensitive method of detecting SLNs. Avoiding the greater frequency of allergic reactions seen with lymphazurin is an important advantage of methylene blue.