Marc-Antoine Allard

Impact of clinically evident portal hypertension on the course of hepatocellular carcinoma in patients listed for liver transplantation

Liver transplantation (LT) is the best curative treatment for early hepatocellular carcinoma (HCC) in patients with cirrhosis. However, the current shortage of organs causes prolonged waiting times and poorer intention‐to‐treat (ITT) survival (i.e., after listing) owing to tumor progression and dropout. Portal hypertension (PH) is a recognized risk factor of HCC development in patients with cirrhosis and its recurrence after resection. The aim of this study was to evaluate the potential impact of PHT on the results of LT on an ITT basis. Patients with cirrhosis listed for LT for HCC were included and their outcomes after listing were compared according to the presence or absence of PH defined as presence of esophageal varices or ascites or low platelet count and splenomegaly. Among 243 consecutively listed patients, 70% were affected by PH, which was associated with a significantly higher risk of tumor progression (38% vs. 22%; P = 0.017) and a higher risk of dropout (22% vs. 8%; P = 0.01). Transarterial chemoembolization (TACE) was similarly applied to the two groups (60% vs. 67%; P = 0.325). An absence of TACE was the only other independent risk factor of dropout owing to tumor progression. Under an ITT analysis, PH reduced overall survival (OS), but there was no difference in OS and time to recurrence post‐LT. The only pathological feature that could potentially explain this observation was the lower complete response to TACE in the PHT group (12% vs. 36%; P = 0.001). Conclusion: PH should be regarded as a major risk factor of dropout owing to tumor progression and should be taken into consideration when managing patients with HCC who are waiting for LT. (Hepatology 2015;62:179‐187)

Evidence of intermetastatic heterogeneity for pathological response and genetic mutations within colorectal liver metastases following preoperative chemotherapy

Background In patients receiving preoperative chemotherapy, colorectal liver metastases (CLM) are expected to demonstrate a similar behaviour because of similar organ microenvironment and tumour cell chemosensitivity. We focused on the occurrence of pathological and genetic heterogeneity within CLM. Methods Patients resected for multiple CLM between 2004 and 2011 after > three cycles of chemotherapy were included. Pathological heterogeneity was arbitrarily defined as a > 50% difference in the percentage of remaining tumour cells between individual CLM. In patients with pathological heterogeneity, the mutational genotyping (KRAS, NRAS, BRAF and PIK3CA) was determined from the most heterogeneous CLM. Results Pathological heterogeneity was observed in 31 of 157 patients with multiple CLM (median = 4, range, 2–32) (19.7%). In 72.4% of them, we found a concordance of the mutation status between the paired CLM: both wild-type in 55%, and both mutated in 17.2%. We observed a discordance of the mutation status of 27.6% between CLM: one mutated and the other wild-type. The mutated CLM was the less florid one in 75% of patients with genetic heterogeneity. Conclusions Pathological heterogeneity is present in 19.7% of patients with multiple CLM. Genetic heterogeneity is present in 27.6% of patients with pathological heterogeneity. Heterogeneity could refine guide management for tissue sampling.

Incidence and prognosis of synchronous colorectal carcinomatosis

The aim of this article was to review the literature on synchronous peritoneal carcinomatosis (PC) from colorectal cancer. Synchronous PC of colorectal cancer origin is a rare disease with an incidence ranging from 4 to 7% of colorectal cancer patients and is exclusively peritoneal in half of cases. Synchronous PC is more frequently associated with primary tumors that are at an advanced stage. After macroscopically complete resection (R0/R1) of synchronous PC, without associated intraperitoneal chemotherapy, the 5-year survival rates range from 24 to 36%. Complete cytoreductive surgery plus intraperitoneal chemotherapy at the time of diagnosis is probably the best therapeutic option. If no intraperitoneal treatment can be given, no resection should be performed and an accurate description should be made. If a limited synchronous PC has been resected with the primary tumor without intraperitoneal treatment, the authors recommend a systematic second-look surgery in an experienced center.

Rare genetic heterogeneity within single tumor discovered for the first time in colorectal liver metastases after liver resection

Effective individualized treatment of patients with colorectal liver metastases (CLM) requires tumor genotyping, usually based on the analysis of one single sample per patient. Therapy failure may partially be explained by sampling errors and/or intratumoral genetic heterogeneity. We aimed to demonstrate intratumoral genetic heterogeneity in CLM and enable pathologists to select tumor tissue for genotyping. All the tumors of 86 patients who underwent liver resection for a single CLM were reviewed. Of the 86 patients, 66 patients received chemotherapy and 20 patients did not receive chemotherapy before liver resection. All the tumor areas sampled were analyzed for KRAS, BRAF, PIK3CA, and NRAS mutations. The mutational status was tested in 74 cases, 7 cases had no tumoral cells due to complete responses and 5 blocks were unavailable. Of the 59/74 CLM with > 1 sample, 56 showed the same mutational status between the samples. The remaining 3 cases (5% of all cases) showed genetic heterogeneity for KRAS in 2 and BRAF in 1 patient. Genetic heterogeneity correlated with lower rate of viable tumor cells (p=0.009) and higher rate of mucin pools (p=0.013). We demonstrate for the first time the existence of genetic intratumoral heterogeneity in 5% of CLM. In routine practice, this low incidence does not require the genotyping of additional tumor samples. The correlation between the genetic heterogeneity and some histological components of the CLM should be verified by further in situ mutation assay.

Comment on “Long-Term Survival Benefit and Potential for Cure after R1 Resection for Colorectal Liver Metastases”: A Reply

We read with interest the letter of Cucchetti et al. regarding our article published in Annals of Surgical Oncology, and thank the authors for their suggestions and comments. We agree that, in epidemiology, cure occurs when the mortality of patients treated for a specific disease returns to the same level as that of the general population. Furthermore, we respect the authors’ efforts to define statistical cure after R0 resection for colorectal liver metastases (CLM) using a cure-rate model. However, we are concerned that the authors’ definition may limit its use in daily clinical practice, for the following two reasons. First, their definition of cure after resection for CLM can only be used for patients undergoing initial hepatectomy and cannot be applied to patients after resection for recurrent CLM. Because CLM represents a systemic disease, the incidence of recurrence is as high as 75%, even after curative resection. However, the development of a first relapse after initial hepatectomy does not reflect surgical failure or non-curability because repeat resection for recurrent disease has been accepted as providing a survival benefit and another chance for cure. As our definition could define CLM patients with long-term remission after resection of recurrent disease as ‘potentially cured’, the practical definition of cure after resection for CLM should consider not only cure after initial hepatectomy but also cure after resection for recurrent disease. Second, the authors’ definition of cure cannot be used for patients after R1 resection, which includes 10–24% of patients who undergo surgical resection for CLM. As shown in our report, potential cure was possible in 18% of patients, even after R1 resection therefore, the practical definition of cure should be applicable to patients following resection for CLM, regardless of margin status. We defined cure after resection for CLM as a diseasefree survival interval of at least 5 years since the last treatment for CLM. We believe that this endpoint may be a surrogate for potential cure after resection for CLM because 120 of the 122 disease recurrences (98%) observed in our series occurred within the first 5 years of patient follow-up. Furthermore, as mentioned, our definition could also define eight patients (five patients after second hepatectomy, one after third hepatectomy, and two after resection of extrahepatic disease recurrence) with longterm remission after repeat resection for recurrent disease as potentially cured. Therefore, our definition of cure after resection for CLM appears to be clinically more useful; however, this definition needs to be validated in another independent patient cohort. A final comment concerns cure after resection for CLM. Both studies showed similar rates of cure (23% for R0 resection and 18% for R1 resection, and 20% for R0 resection) and clearly demonstrated that only surgical resection offers the best chance for cure in patients with CLM. Therefore, our goal is to increase the number of patients with CLM being offered surgical resection with curative intent. Sincerely, Isamu Hosokawa, MD, PhD René Adam, MD, PhD Society of Surgical Oncology 2017

Abstract P4-05-14: The PI3KCA mutations are frequent and remain along with recurrence of liver metastases from breast cancer in women who underwent up to 3 liver resections

The Liver resection associated with anticancer and hormonal treatments for metastatic breast cancer results in improved patient survival. However, many patients have tumor recurrence. The frequently observed mutations in PIK3CA that have been associated with resistance to chemotherapy and to anti-HER2 or anti-estrogen therapies treatment, could be involved in the recurrence of liver metastases (and targeted in the future). Therefore, we have analyzed the incidence of the two major 9hot spot9 mutations in the helical and catalytic domains of PI3KCA in the liver metastases from breast cancer (LMBC) isolated in a selected cohort of 20 women who underwent at least 2 liver resections with curative intent. Twelve of them had a third hepatectomy. The first hepatectomy was between 1 to 6 yrs after the diagnosis of primary tumors. A total of 73 LMBC were analyzed. The characteristics of the LMBC at the first hepatectomy : the median age was 52 yrs (range: 30 to 64). Five patients had a solitary tumor whereas the others had up to 5 nodules. The tumor stages varied from stage IA to IIIA and were ductal tumors for 80% of them. Hormonal status varied from the negativity for the receptors to estrogen (ER), progesterone (PR) and HER2 (n=4), to the clearcut positivity ER (n=2), PR (n=3), HER2 (n=4). Out of 20 patients, 6 had LMBC carrying PI3KCA mutations (1 H1047R, 6 E545K). When LMBC were multinodular, all the nodules except one harbored the PI3KCA mutation. The characteristics of the recurrent LMBC: out of the 6 LMBC with PI3KCA mutations, 4 recurred and underwent a third hepatectomy. One patient whose LMBC did not harbor any PI3KCA mutations at the first liver resection had mutant PI3KCA in the LMBC from the second to the fourth liver resection. All the nodules of the 5 women harbored the same PI3KCA mutation. In parallel, 7 women underwent a third liver resection with no PI3KCA mutations in any of the nodules analyzed. There was no relationship between the recurrence of LMBC with PI3KCA mutations and the surgical margins. The frequency of women whose LMBC carry PI3KCA mutations increased at the third hepatectomy In conclusion, PI3KCA mutations are frequently observed in LMBC in all the nodules and persist along with the recurrence. However, PI3KCA could constitute a new target in the neoadjuvant setting before hepatectomy. Citation Format: Archie Ruiz, Mylene Sebagh, Raphael Saffroy, Marc-Antoine Allard, Philippe Bouvet De La Maisonneuve, Nelly Bosselut, Rene Adam, Antoinette Lemoine, Jean-Francois Morere. The PI3KCA mutations are frequent and remain along with recurrence of liver metastases from breast cancer in women who underwent up to 3 liver resections [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-05-14.