Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets

Background

The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.

Methods

Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined.

Results

The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis.

Conclusions

Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.     

Impact of Bilateral Versus Unilateral Mastectomy on Short Term Outcomes and Adjuvant Therapy, 2003–2010: A Report from the National Cancer Data Base

Background

Rates of bilateral mastectomy (BM) have increased, but the impact on length of stay (LOS), readmission rate, 30-day mortality, and time to adjuvant therapy is unknown.

Methods

Using the National Cancer Data Base, we selected 390,712 non-neoadjuvant AJCC stage 0–III breast cancer patients who underwent either unilateral mastectomy (UM) or BM from 2003 to 2010 with and without reconstruction. We used chi-square and logistic regression models for the analysis.

Results

A total of 315,278 patients (81 %) had UM, and 75,437 (19 %) had BM; 97,031 (25 %) underwent reconstruction. The number of median days from diagnosis to UM increased from 19 days in 2003 to 28 days in 2010, and for BM, increased from 21 to 31 days (p < 0.001). BM was independently associated with a longer time to surgery when adjusting for patient, facility, and tumor factors and reconstruction (OR 1.11; 95 % CI 1.07–1.15; p < 0.001). Reconstructed patients were twice as likely to have a longer time to surgery (OR 2.07; 95 % CI 2.01–2.14; p < 0.001). The median LOS was 1 day (range 0–184 days) for UM versus 2 (range 0–182) for BM (p < 0.001); 30-day mortality and readmission rates were not different between BM and UM. The median number of days from diagnosis to definitive chemotherapy, hormonal therapy, and radiation therapy was significantly greater in the BM group.

Conclusions

Delays to surgical and adjuvant treatment are significantly longer for BM irrespective of reconstruction, and these delays have increased over the study period. These findings can be used by clinicians to counsel patients on BM.     

Cost of Contralateral Prophylactic Mastectomy

Purpose

To compare the healthcare costs of women with unilateral breast cancer who underwent contralateral prophylactic mastectomy (CPM) with those of women who did not.

Methods

We conducted a retrospective study of 904 women treated for stage I–III breast cancer with or without CPM. Women were matched according to age, year at diagnosis, stage, and receipt of chemotherapy. We included healthcare costs starting from the date of surgery to 24 months. We identified whether care was immediate or delayed (CPM within 6 months or 6–24 months after initial surgery, respectively). Costs were converted to approximate Medicare reimbursement values and adjusted for inflation. Multivariable regression analysis was performed to evaluate the effect of CPM on total breast cancer care costs adjusting for patient characteristics and accounting for matched pairs.

Results

The mean difference between the CPM and no-CPM matched groups was $3,573 (standard error [SE] $455) for professional costs, $4,176 (SE $1,724) for technical costs, and $7,749 (SE $2,069) for total costs. For immediate and delayed CPM, the mean difference for total costs was $6,528 (SE $2,243) and $16,744 (SE $5,017), respectively. In multivariable analysis, the CPM group had a statistically significant increase of 16.9 % in mean total costs compared with the no-CPM group (p < 0.0001). Human epidermal growth factor receptor 2/neu-positive status, receipt of radiation, and reconstruction were associated with increases in total costs.

Conclusions

CPM significantly increases short-term healthcare costs for women with unilateral breast cancer. These patient-level cost results can be used for future studies that evaluate the influence of costs of CPM on decision making.     

Recurrence Patterns and Prognostic Factors in Patients with Hepatocellular Carcinoma in Noncirrhotic Liver: A Multi-Institutional Analysis

Background

Hepatocellular carcinoma (HCC) primarily affects patients with a cirrhotic liver. Reports on the characteristics of patients with HCC in noncirrhotic liver, as well as predictors of recurrence and survival, are scarce.

Methods

Between 1992 and 2011, 334 patients treated for HCC in noncirrhotic liver were identified from three major hepatobiliary centers. Clinicopathological characteristics were analyzed and independent predictors of recurrence and overall survival were identified using Cox proportional hazards models.

Results

Median patient age was 58 years and 77 % were male. Most patients had a solitary (81 %) and poorly or undifferentiated tumor (56 %); median size was 6.5 cm. The majority of patients (96 %) underwent liver resection (microscopically negative margins in 94 %), whereas a few had transarterial chemoembolization or transplantation (4 %). Median recurrence-free survival (RFS) was 2.5 years, and 1- and 5-year RFS was 71.1, and 35 %, respectively. Elevated alkaline phosphatase levels [hazards ratio (HR) = 1.82], poor tumor differentiation (HR = 1.4), macrovascular invasion (HR = 2.18), and the presence of satellite lesions (HR = 1.9), or intrahepatic metastases (HR = 2.59) were independently associated with shorter RFS; in contrast, an intact tumor capsule independently prolonged RFS (HR = 0.46). Median overall survival was 5.9 years, and 1- and 5-year overall survival was 86.9, and 54.5 %, respectively. Tumor size ≥5 cm (HR = 2.27), macrovascular (HR = 2.72) or adjacent organ invasion (HR = 3.34), and satellite lesions (HR = 2.18) were independently associated with shorter overall survival, whereas an intact tumor capsule showed a protective effect (HR = 0.51).

Conclusions

Following resection of HCC in the setting of no cirrhosis, more than one-half of patients were alive after 5 years. However, even among patients with no cirrhosis, recurrence was common. Factors associated with RFS and overall survival included tumor characteristics, such as tumor capsule, satellite lesions, and vascular invasion.     

Treatment Patterns and Outcomes for Patients with Adrenocortical Carcinoma Associated with Hospital Case Volume in the United States

Background

Adrenocortical carcinoma (ACC) is a rare, aggressive disease with no apparent change in treatment or survival in the United States over the past two decades. Our objective was to determine whether treatment patterns or clinical outcomes vary by hospital case volume.

Methods

Patients with ACC were identified from the National Cancer Database (1998–2011). High-volume centers (HVCs) were defined by a case load of ≥4 cases of primary adrenal malignancy annually, which corresponded to the 90th percentile. All other facilities were considered low-volume centers (LVCs).

Results

A total of 2,765 ACC patients were treated across 1,046 facilities. Compared to patients treated at LVCs, patients treated at HVCs were younger (50 vs. 54 years), with larger tumors (11.2 vs. 10.5 cm), and underwent higher rates of surgery (78.8 vs. 73.4 %), radical resection (17.3 vs. 13.9 %), regional lymph node evaluation (23.2 vs. 18.8 %), and chemotherapy including mitotane (43.8 vs. 31.0 %, all p < 0.05).There were no significant differences in median length of stay (5 vs. 5 days), 30-day readmission rates (4.0 % for HVCs vs. 3.9 % for LVCs), or 30-day postoperative mortality rates (1.9 % for HVCs vs. 3.7 % for LVCs). Median overall survival was 2.0 years for HVCs and 1.9 years for LVCs, p = 0.53. After adjusting for patient and tumor characteristics, overall survival did not differ significantly between patients treated at HVCs versus LVCs [HR = 0.89 (95 % confidence interval 0.70, 1.12)].

Conclusions

Treatment at HVCs was associated with more aggressive surgical resection and chemotherapy use. Prognosis remained poor despite more aggressive treatment.     

Genitourinary Resection at the Time of Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis Is Not Associated with Increased Morbidity or Worsened Oncologic Outcomes: A Case-matched Study

Background

Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) has gained acceptance in the treatment of peritoneal carcinomatosis with reported morbidity and mortality rates of 27–56 and 0–11 %, respectively. The safety and oncologic outcome of genitourinary repair at the time of CRS and HIPEC remains unclear.

Methods

We identified 170 patients who underwent CRS-HIPEC at our institution between July 2007 and August 2011 with a minimum follow-up of 6 months. Thirty-four (20 %) underwent concomitant urologic reconstruction at the time of CRS-HIPEC and were matched by disease burden (intraoperative peritoneal cancer index [PCI]) and extent of surgery (ΔPCI) with a cohort of 38 (22.3 %) subjects without genitourinary involvement. The primary end points considered for this analysis included the development of major surgical (Clavien–Dindo Class III–V) complications and overall survival.

Results

Median follow-up was 9.4 months. The most commonly performed urologic interventions included partial cystectomy with primary repair in 23 (65.7 %) and segmental ureteral resection and repair in 11 (31.4 %). Patients with genitourinary reconstruction had more total organ involvement (6.5 vs. 4.3, p < 0.001) and more commonly underwent enteric anastomoses (82.4 vs. 57.9 %, p = 0.025). No significant differences were observed with regard to major morbidity, need for transfusion, operative time, intensive care unit admission, or length of stay. Among patients with appendiceal or colonic tumors (n = 46), overall survival was similar between genitourinary reconstruction and matched cohorts: 22.5 versus 15.1 months, respectively (p = 0.66).

Conclusions

Genitourinary reconstruction at the time of CRS-HIPEC occurs more commonly in patients with extensive disease burden undergoing radical debulking, yet does not adversely influence surgical morbidity or survival.     

Use of Prophylactic Postoperative Antibiotics During Surgical Drain Presence Following Mastectomy

Background

National guidelines recommend one dose of perioperative antibiotics for breast surgery and discourage postoperative continuation. However, reported skin and soft tissue infection (SSI) rates after mastectomy range from 1–26 %, higher than expected for clean cases. Utility of routine or selective postoperative antibiotic use for duration of drain presence following mastectomy remains uncertain.

Methods

This study included all female patients who underwent mastectomy without reconstruction at our institution between 2005 and 2012. SSI was defined using CDC criteria or clinical diagnosis of cellulitis. Information on risk factors for infection (age, body mass index [BMI], smoking status, diabetes, steroid use), prior breast cancer treatment, drain duration, and antibiotic use was abstracted from medical records. Multivariable logistic regression was used to assess the association between postoperative antibiotic use and the occurrence of SSI, adjusting for concurrent risk factors.

Results

Among 480 patients undergoing mastectomy without reconstruction, 425 had sufficient documentation for analysis. Of these, 268 were prescribed antibiotics (63 %) at hospital discharge. An overall SSI rate of 7.3 % was observed, with 14 % of patients without postoperative antibiotics developing SSI compared with 3.4 % with antibiotics (p < 0.0001). Factors independently associated with SSI were smoking and advancing age. Diabetes, steroid use, BMI, prior breast surgery, neoadjuvant chemotherapy, prior radiation, concomitant axillary surgery, and drain duration were not associated with increased SSI rates.

Conclusions

SSI rates among patients who did and did not receive postoperative antibiotics after mastectomy were significantly different, particularly among smokers and women of advanced age. These patient subgroups may warrant special consideration for postoperative antibiotics.     

Management of Positive Sub‐areolar/Nipple Duct Margins in Nipple‐Sparing Mastectomies

We evaluated management of positive sub‐areolar/nipple duct margins in nipple‐sparing mastectomies (NSM) at our institution. Retrospective chart review of all NSM from January 2007 to April 2012 was performed and patient, tumor, and treatment information was collected. Sub‐areolar/nipple duct margins included ductal tissue from within the nipple. Of 438 NSM, 22 (5%) had positive sub‐areolar/nipple duct margins; 21 of 220 cancer‐bearing breasts (10%) and 1 of 218 prophylactic mastectomies (0.5%). Positive margins included four with invasive lobular carcinoma and 18 with ductal carcinoma in situ (DCIS). Management included removal of eight nipples and nine nipple areola complexes (NAC). Four of 17 nipple/NAC specimens had evidence of residual DCIS and none had residual invasive cancer. The majority of nipple/NAC specimens excised for a positive margin had no residual malignancy. Future studies are needed to determine the extent of NAC tissue removal required for positive margins.     

Risk of Positive Nonsentinel Nodes in Women with 1–2 Positive Sentinel Nodes Related to Age and Molecular Subtype Approximated by Receptor Status

We examine risk of positive nonsentinel axillary nodes (NSN) and ≥4 positive nodes in patients with 1–2 positive sentinel nodes (SN) by age and tumor subtype approximated by ER, PR, and Her2 receptor status. Review of two institutional databases demonstrated 284 women undergoing breast conservation between 1997 and 2008 for T1‐2 tumors and 1 (229) or 2 (55) positive SN followed by completion dissection. The median number of SN and total axillary nodes removed were 2 (range 1–10) and 14 (range 6–37), respectively. The rate of positive NSNs (p = 0.5) or ≥4 positive nodes (p = 0.6) was not associated with age. NSN were positive in 36% of luminal A, 26% of luminal B, 21% of TN and 38% of Her2+ (p = 0.4). Four or more nodes were present in 17% of luminal A, 13% luminal of B, 0% of TN and 29% of Her2+ (p = 0.1). Microscopic extracapsular extension was significantly associated with having NSNs positive (55% versus 24%, p < 0.0001) and with having total ≥4 nodes positive (33% versus 7%, p < 0.0001). In a population that was largely eligible for ACOSOG Z0011, the risk of positive NSN or ≥4 positive nodes did not vary significantly by age. The TN subgroup had the lowest risk of both positive NSN or ≥4 positive nodes. Several high risk groups with >15% risk for having ≥4 positive nodes were identified. Further data is needed to confirm that ACOSOG Z0011 results are equally applicable to all molecular phenotypes.