Evaluation of invasive breast cancer samples using a 12-chemokine gene expression score: correlation with clinical outcomes.

BACKGROUND: A unique 12-chemokine gene expression score (CS) accurately predicted the presence of tumor-localized, ectopic lymph node-like structures (TL-ELNs) and improved overall survival (OS) in primary colorectal cancer and metastatic melanoma. We analyzed the correlation between CS, clinicopathological variables, molecular data, and 366 survival in Moffitt Cancer Center's Total Cancer Care (TCC) patients with non-metastatic breast cancer. METHODS: Affymetrix gene expression profiles were used to interrogate the CS by the principal component method. Breast tumors were classified as high or low score based on median split, and correlations between clinicopathologic variables, PAM50 molecular subtype, and ELN formation were analyzed using the TCC dataset. Differences in overall survival (OS) and recurrence-free survival (RFS) in the larger KM Plot breast cancer public datasets were compared using Kaplan-Meier curves. RESULTS: We divided the Total Cancer Care (TCC) breast cancer patients into two groups of high or low CS. Mean CS was 0.24 (range, 2.2-2.1). Patients with higher CS were more likely to be white (172 vs. 159; p = 0.03), had poorly differentiated tumors (112 vs. 59; p <0.0001), ER/PR negative (41 vs. 26) and HER2 positive (36 vs. 19; p = 0.001), and contain TL-ELNs. Higher CS scores were also seen in the basal and HER2+ molecular subtypes. In the KM Plot breast cancer datasets higher CS patients demonstrated superior OS (HR = 0.73, p = 0.008) and RFS (HR 0.76, p = <0.0001), especially in basal and HER2+ patients. CONCLUSIONS: High CS breast tumors tend to be higher grade, basal or HER2+, and present more frequently in Caucasians. However, this group of patients also shows the presence of TL-ELNs within the tumor microenvironment and has better survival outcomes. The CS is a novel tool that can identify breast cancer patients with tumors of a unique intratumoral immune composition and better prognosis. Whether or not the CS is a predictive response marker in breast cancer patients undergoing immunotherapy remains to be determined.

Single Institution Review of Patients With Prior Breast Augmentation Undergoing Breast Conservation Therapy for Breast Cancer.

BACKGROUND: Increasing number of patients with preexisting breast implants desire breast conservation therapy for breast cancer. There is paucity of comparative data on tumor margins and re-excisions in these patients. High re-excision rates up to 25% have been reported in breast conservation therapy patients; efforts to obtain cosmesis and avoid implant rupture might increase this further. We analyzed tumor margins, re-excision rates, and recurrence in previously augmented versus non-augmented patients undergoing lumpectomy for breast cancer. We preserved preexisting implants if feasible with oncologic clearance and cosmesis. METHODS: Institutional review board-approved retrospective analysis was performed on patients undergoing lumpectomy with history of prior breast augmentation (N = 52) and consecutively selected non-augmented patients (N = 51). Based on tumor distance to inked margin, we grouped margins as negative (≥2 mm), close (<2 mm), and positive. Patients were followed up clinically and with imaging in the outpatient clinic, and recurrences were documented. RESULTS: Patients in the non-augmented group were significantly more likely to have larger tumors (T2 and above; P = 0.05) compared with the augmented group. Although more patients in the augmented group had positive margins, this was not statistically significant (6 vs 3, P = 0.86). No difference was noted between re-excision rates among the augmented versus non-augmented groups (21.1% vs 19.6%, respectively; odds ratio, 0.91; 95% confidence interval, 0.35-2.37; P = 0.85); these remained unchanged even when adjusting for tumor stage (P = .75) and margins (P = 0.73). Although more patients in the augmented group recurred (4 vs 0), this was not statistically significant (P = 0.1). CONCLUSIONS: Our results indicate that, from the oncological standpoint, patients with prior augmentation can undergo lumpectomy with equivalent tumor margins and re-excision rates. To the best of our knowledge, this is the first reported comparative study between these 2 groups.

Complications and Recurrence in Implant-Sparing Oncologic Breast Surgery.

BACKGROUND: Patients with a history of prior breast augmentation and newly diagnosed breast cancer represent a rapidly expanding and unique subset of patients. Prior studies have described changes in breast parenchyma and characteristic body habitus of previously augmented patients, as well as increased rates of capsular contracture associated with breast conservation therapy. In our current study, we aimed to study the risk factors contributing to morbidity and whether recurrence rates are higher in patients with prior breast augmentation undergoing lumpectomy or mastectomy for breast cancer and identify differences in complications between these 2 groups. METHODS: Retrospective analysis approved by institutional review board was performed on patients with prior breast augmentation undergoing lumpectomy (N = 52) and mastectomy (N = 64) for breast cancer. RESULTS: Patients with prior breast augmentation undergoing mastectomy had a higher rate of complications compared with those undergoing lumpectomy (20.3% vs 5.9% respectively, P = 0.031), after adjusting for patient-specific factors including body mass index [odds ratio (OR), 0.242; 95% confidence interval (CI), 0.063-0.922; P = 0.0376], tumor stage (OR, 0.257; 95% CI, 0.064-1.036; P = 0.0562), smoking status (OR, 0.244; 95% CI, 0.065-0.918; P = 0.0370), and chemotherapy (OR, 0.242; 95% CI, 0.064-0.914; P = 0.0364). Four patients (7.7%) developed late complications in the lumpectomy group with 2 developing capsular contractures, 1 had fat necrosis and 1 needed complex reconstruction because of flattening of the nipple-areolar complex. There was no difference in recurrence or tumor margins between lumpectomy and mastectomy groups. CONCLUSIONS: Patients with prior breast augmentation undergoing mastectomy have higher complication rates compared with lumpectomy even after adjusting for tumor stage. There appears to be no increased oncologic risk associated with either procedure given our current follow-up. Understanding these operative risks may help in patients' decision-making process with regards to type of oncologic surgery.

Comparison of Reconstructive Outcomes in Breast Cancer Patients With Preexisting Subpectoral Implants: Implant-Sparing Mastectomy With Delayed Implant Exchange Versus Immediate Tissue Expander Reconstruction.

BACKGROUND: Women who have undergone prior augmentation mammoplasty represent a unique subset of breast cancer patients with several options available for breast reconstruction. We performed a single institution review of surgical outcomes of breast reconstruction performed in patients with breast cancer with prior history of subpectoral breast augmentation. METHODS: Institutional review board-approved retrospective review was conducted among patients with previously mentioned criteria treated at our institution between 2000 and 2014. Reconstructions were grouped into 2 categories as follows: (1) removal of preexisting subpectoral implant during mastectomy with immediate tissue expander placement and (2) implant-sparing mastectomy followed by delayed exchange to a larger implant. We reviewed demographics, tumor features, and reconstruction outcomes of these groups. RESULTS: Fifty-three patients had preexisting subpectoral implants. Of the 63 breast reconstructions performed, 18 (28.6%) had immediate tissue expander placed and 45 (71.4%) had implant-sparing mastectomy followed by delayed implant exchange. The groups were comparable based on age, body mass index, cancer type, tumor grade, TNM stage at presentation, and hormonal receptor status. No significant difference was noted between tumor margins or subsequent recurrence, mastectomy specimen weight, removed implant volume, volume of implant placed during reconstruction, or time from mastectomy to final implant placement. Rates of complications were significantly higher in the tissue expander group compared to the implant-sparing mastectomy group 7 (38.9%) versus 4 (8.9%) (P = 0.005). CONCLUSIONS: Implant-sparing mastectomy with delayed implant exchange in patients with preexisting subpectoral implants is safe and has fewer complications compared to tissue expander placement. There was no difference noted in the final volume of implant placed, time interval for final implant placement, or tumor margins.

Outcomes of Breast Reconstruction After Mastectomy Using Tissue Expander and Implant Reconstruction.

OBJECTIVE: Considerable attention has been given to patient-reported outcomes in breast reconstruction. The objective of this study is to evaluate the effect of postreconstruction change in breast volume on validated patient satisfaction survey scores. METHODS: Patients undergoing skin-sparing mastectomy followed by tissue expander/implant reconstruction between July 2010 and July 2014 by a single surgeon were given postoperative patient-reported satisfaction surveys (BREAST-Q). Retrospective chart review of patients with completed surveys was undertaken to record patient characteristics and compare preoperative breast volume (extrapolated from mastectomy mass) with postoperative implant volume, and percent change in volume was calculated. Regressions were utilized to correlate percent change with satisfaction in each category. RESULTS: A total of 160 patient surveys were included. Sixty-five percent of breasts analyzed had increased volume after reconstruction, whereas 35% had decreased volume. The increased volume group had significantly lower body mass index (P = 0.0001) and was significantly younger (P = 0.009) than the decreased volume group. Patients who experienced increase in breast volume reported statistically greater satisfaction with breasts (P = 0.019), overall outcome (P = 0.012), sexual well-being (P = 0.002), and information (P = 0.042) compared with the decreased volume group. Moreover, linear regression revealed that as percent change increased, so did satisfaction with outcome (P = 0.02), sexual well-being (P = 0.005), information (P = 0.018), and surgeon (P = 0.036). Notably, there was not a significant difference in complication rate (P = 0.146) or tumor margin (0.914) between the groups. CONCLUSION: Patients who undergo tissue expander/implant breast reconstruction with final implants that are larger in volume than their native breasts have increased patient satisfaction scores in several categories without increase in complication rate or difference in tumor margin. There is a positive linear relationship between percent change and patient satisfaction.

Precision Medicine in Colorectal Surgery.

This article reviews advances in precision medicine for colorectal carcinoma that have influenced screening and treatment, and potentially prevention. Advances in molecular techniques have made it possible for better patient selection for therapies; therefore, mutational analysis should be performed at diagnosis to guide treatment. Future efforts should focus on validating these treatments in specific subgroups and on understanding the mechanisms of resistance to therapies to enable treatment optimization, promote efficacy, and reduce treatment costs and toxicities.

Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy.

If we build it they will come: targeting the immune response to breast cancer.

Historically, breast cancer tumors have been considered immunologically quiescent, with the majority of tumors demonstrating low lymphocyte infiltration, low mutational burden, and modest objective response rates to anti-PD-1/PD-L1 monotherapy. Tumor and immunologic profiling has shed light on potential mechanisms of immune evasion in breast cancer, as well as unique aspects of the tumor microenvironment (TME). These include elements associated with antigen processing and presentation as well as immunosuppressive elements, which may be targeted therapeutically. Examples of such therapeutic strategies include efforts to (1) expand effector T-cells, natural killer (NK) cells and immunostimulatory dendritic cells (DCs), (2) improve antigen presentation, and (3) decrease inhibitory cytokines, tumor-associated M2 macrophages, regulatory T- and B-cells and myeloid derived suppressor cells (MDSCs). The goal of these approaches is to alter the TME, thereby making breast tumors more responsive to immunotherapy. In this review, we summarize key developments in our understanding of antitumor immunity in breast cancer, as well as emerging therapeutic modalities that may leverage that understanding to overcome immunologic resistance.

Two may be better than one: PD-1/PD-L1 blockade combination approaches in metastatic breast cancer.

Antibodies blocking programmed death 1 (anti-PD-1) or its ligand (anti-PD-L1) are associated with modest response rates as monotherapy in metastatic breast cancer, but are generally well tolerated and capable of generating dramatic and durable benefit in a minority of patients. Anti-PD-1/L1 antibodies are also safe when administered in combination with a variety of systemic therapies (chemotherapy, targeted therapies), as well as with radiotherapy. We summarize preclinical, translational, and preliminary clinical data in support of combination approaches with anti-PD-1/L1 in metastatic breast cancer, focusing on potential mechanisms of synergy, and considerations for clinical practice and future investigation.

Combination of Ipilimumab and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma.

PURPOSE: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) for metastatic melanoma can be highly effective, but attrition due to progression before TIL administration (32% in prior institutional experience) remains a limitation. We hypothesized that combining ACT with cytotoxic T lymphocyte-associated antigen 4 blockade would decrease attrition and allow more patients to receive TIL. EXPERIMENTAL DESIGN: Thirteen patients with metastatic melanoma were enrolled. Patients received four doses of ipilimumab (3 mg/kg) beginning 2 weeks prior to tumor resection for TIL generation, then 1 week after resection, and 2 and 5 weeks after preconditioning chemotherapy and TIL infusion followed by interleukin-2. The primary endpoint was safety and feasibility. Secondary endpoints included of clinical response at 12 weeks and at 1 year after TIL transfer, progression free survival (PFS), and overall survival (OS). RESULTS: All patients received at least two doses of ipilimumab, and 12 of the 13 (92%) received TIL. A median of 6.5 × 1010 (2.3 × 1010 to 1.0 × 1011) TIL were infused. At 12 weeks following infusion, there were five patients who experienced objective response (38.5%), four of whom continued in objective response at 1 year and one of which became a complete response at 52 months. Median progression-free survival was 7.3 months (95% CI 6.1-29.9 months). Grade ≥ 3 immune-related adverse events included hypothyroidism (3), hepatitis (2), uveitis (1), and colitis (1). CONCLUSION: Ipilimumab plus ACT for metastatic melanoma is feasible, well tolerated, and associated with a low rate of attrition due to progression during cell expansion. This combination approach serves as a model for future efforts to improve the efficacy of ACT.

Resection of Gastrointestinal Metastases in Stage IV Melanoma: Correlation with Outcomes.

The prognosis of patients with gastrointestinal (GI) melanoma metastases is poor. Surgery renders select patients disease free and/or palliates symptoms. We reviewed our single-institution experience of resection with GI melanoma metastases. A retrospective review was performed on patients who underwent surgery for GI melanoma metastases from 2007 to 2013. Fifty-four patients were identified and separated based on completeness of resection into curative 13 (24%) and palliative 41 (75.9%) groups. Thiry-six (63.2%) were symptomatic preoperatively with bleeding and/or obstruction/pain with 91.7 per cent achieving objective symptom relief. Thirty-day operative mortality was 0 per cent. The most common complication was wound infection (n = 5); major complications like anastomotic leak (n = 1) were uncommon. With a median follow-up of 9.5 months (range 0.2-75.8), median overall survival was not reached (curative) versus 9.53 months (palliative group). Median recurrence-free and progression-free survival after resection were 18.89 and 1.97 months in the curative versus palliative groups, respectively. On multivariate analysis, resection to no clinical evidence of disease (P = 0.012) and presence of single metastases (P = 0.031) were associated with improved overall survival. Surgery for GI metastases from melanoma provides symptomatic relief without major morbidity. Fewer metastases and curative resection were associated with improved survival.