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Genomic portfolio of Merkel cell carcinoma as determined by comprehensive genomic profiling: implications for targeted therapeutics

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Oncotarget. 2016; 7:23454-23467. https://doi.org/10.18632/oncotarget.8032

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Philip R. Cohen _, Brett N. Tomson, Sheryl K. Elkin, Erica Marchlik, Jennifer L. Carter and Razelle Kurzrock

Abstract

Philip R. Cohen1, Brett N. Tomson2, Sheryl K. Elkin2, Erica Marchlik2, Jennifer L. Carter2, Razelle Kurzrock3

1Department of Dermatology, University of California San Diego, San Diego, CA, USA

2N-of-One, Inc., Lexington, MA, USA

3Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, San Diego, CA, USA

Correspondence to:

Philip R. Cohen, e-mail: mitehead@gmail.com

Keywords: Merkel cell carcinoma, next-generation sequencing, targeted therapy, personalized therapy, genomic landscape

Received: January 29, 2016     Accepted: February 28, 2016     Published: March 10, 2016

ABSTRACT

Merkel cell carcinoma is an ultra-rare cutaneous neuroendocrine cancer for which approved treatment options are lacking. To better understand potential actionability, the genomic landscape of Merkel cell cancers was assessed. The molecular aberrations in 17 patients with Merkel cell carcinoma were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes) and analyzed by N-of-One, Inc. (Lexington, MA). There were 30 genes harboring aberrations and 60 distinct molecular alterations identified in this patient population. The most common abnormalities involved the TP53 gene (12/17 [71% of patients]) and the cell cycle pathway (CDKN2A/B, CDKN2C or RB1) (12/17 [71%]). Abnormalities also were observed in the PI3K/AKT/mTOR pathway (AKT2, FBXW7, NF1, PIK3CA, PIK3R1, PTEN or RICTOR) (9/17 [53%]) and DNA repair genes (ATM, BAP1, BRCA1/2, CHEK2, FANCA or MLH1) (5/17 [29%]). Possible cognate targeted therapies, including FDA-approved drugs, could be identified in most of the patients (16/17 [94%]). In summary, Merkel cell carcinomas were characterized by multiple distinct aberrations that were unique in the majority of analyzed cases. Most patients had theoretically actionable alterations. These results provide a framework for investigating tailored combinations of matched therapies in Merkel cell carcinoma patients.


Genomic portfolio of Merkel cell carcinoma as determined by comprehensive genomic profiling: implications for targeted therapeutics | Cohen | Oncotarget

INTRODUCTION

Merkel cell carcinoma is an extremely uncommon, biologically aggressive, cutaneous neuroendocrine cancer [14]. It typically presents on sun-exposed skin of elderly men as a rapidly enlarging asymptomatic flesh-colored or blue-red nodule. Local, regional, and distant recurrences are associated with a poor prognostic outcome.

Management for localized disease is surgery: a wide local excision and a sentinel lymph node biopsy. A complete lymph node dissection may follow for patients with a positive sentinel lymph node for cancer. In addition, adjuvant radiation therapy is usually given not only to patients with positive sentinel lymph nodes, but also to patients with Merkel cell carcinoma of the head and neck [14].

For patients with metastatic disease, chemotherapy is used. Unfortunately, after two to three cycles of treatment, resistance frequently develops. In addition to radiation therapy [5, 6], immunotherapy (such as systemic pembrolizumab [MK-3475] a humanized anti-PD1 antibody [7]) and targeted molecular therapy are investigational approaches that have been used for metastatic Merkel cell carcinoma [811].

Due to the rarity of the disease, data regarding response to therapy are often derived from case reports and retrospective series, rather than prospectively performed clinical trials. Thus, it has been challenging to define the role of chemotherapy in management of advanced Merkel cell carcinoma. Systemic chemotherapies currently used include platinum with or without etoposide, as well as cyclophosphamide, doxorubicin and vincristine [35]. Modest responses can be achieved with these cytotoxic agents (median progression-free survival of 3 months). Indeed, there are no drugs approved by the Food and Drug Administration (FDA) specifically for Merkel cell carcinoma.

Importantly, in Merkel cell carcinomas, several molecular abnormalities have been reported [1230]. These include overexpression of Hedgehog (Hh) signal pathway proteins, telomerase activation (TERT), tumor suppressor anomalies (TP53, RB1 and SUFU), and tyrosine kinase signaling activation (AKT, KIT, PDGFRA, PIK3CA and PTEN). In addition, chromosomal abnormalities [29] and microRNA alterations [30] have been demonstrated in Merkel cell carcinomas.

Clinical trials using a variety of targeted tyrosine kinase inhibitors, either as monotherapy or in combination with chemotherapy or one or more additional tyrosine kinase inhibitors, have been initiated for Merkel cell carcinoma. Although a complete response with imatinib (targeting KIT and PDFGR) has been described [31], a low response rate to the agent was observed in a clinical trial [32]. Similarly, a complete response to pazopanib has been observed in Merkel cell carcinoma resistant to chemotherapy [33]; currently, a phase II trail (NCT01841736) is open to evaluate pazopanib in patients with neuroendocrine tumors including Merkel cell carcinoma. However, for several of the current trials, in which these therapies are being given to unselected patients rather than matched to individuals whose tumors harbored cognate aberrations, the results have yet to be reported. Indeed, we are unaware of any trials in which Merkel cell carcinoma patients Merkel cell carcinoma were selected for the presence of specific aberrations and were treated with appropriated targeting agents.

Given that additional effective treatment strategies are needed, the genomic profiles of Merkel cell carcinomas, as determined by comprehensive genomic profiling (targeted next-generation sequencing (NGS)), were examined and the data analyzed in the context of potential actionability.

RESULTS

Genetic aberrations in Merkel cell carcinomas (Tables 1 and 2, Figure 1)

Table 1: Genomic portfolio in each of 17 patients with Merkel cell carcinoma [a]

Abbreviations: C, case; No., number.

[a] 4 cases had more than one molecular aberration in the same gene: case 9 [RB1 = 2], case 13 [TP53 = 3], case 16 [TP53 = 2], and case 17 [TP53 = 2].

[b] Aberration is of uncertain clinical significance and relevance of therapeutic strategies is unknown.

[c] Aberration is an inactivating alteration and therapeutic strategies are not expected to be relevant.

Table 2: Summary of genomic alterations in patients with Merkel cell carcinoma

Aberration

Number of patients

Percent of patients

Potentially actionable [a]

TP53

12

71

Yes

RB1

10

59

No

NOTCH1

3

18

No [b]

PIK3CA

3

18

Yes

BAP1

2

12

Yes

BRCA1/2

2

12

Yes

NF1

2

12

Yes

AKT2

1

6

Yes

ALK

1

6

Yes

APC

1

6

Yes

ARIDIA

1

6

No

ATM

1

6

Yes

CDKN2A/B

1

6

Yes

CDKN2C

1

6

Not clear [c]

CHEK2

1

6

Yes

EGFR

1

6

Yes

EPHAS

1

6

Not clear [c]

FANCA

1

6

Yes

FBXW7

1

6

Yes

KMT2D

1

6

Not clear [c]

MLH1

1

6

Yes

MYC

1

6

No

NTRK3

1

6

Yes

PDGFRB

1

6

Yes

PIK3R1

1

6

Yes

PTCH1

1

6

Yes

PTEN

1

6

Yes

RET

1

6

Yes

RICTOR

1

6

Yes

SMARCA4

1

6

No

[a] Potentially actionable indicates some evidence in the literature that there are drugs that impact the target. This evidence may derive from clinical observations in other tumors or from preclinical evidence.

[b] Activating NOTCH mutations are potentially actionable but the ones in this series were inactivating.

[c] Not clear indicates mixed or inconclusive literature evidence for the potential of available drugs to impact the altered gene product.

Number of patients with each aberration.

Figure 1: Number of patients with each aberration.

Specific genomic abnormalities were observed in all 17 Merkel cell carcinomas and ranged from one to five alterations per tumor; the median was four. Only two patients (cases 2 and 5) had one aberration and only three patients (cases 1, 7 and 15) had two aberrations. Indeed, more than half of the patients (9/17 [53%]) had four or more genetic anomalies.

The most common anomaly among all Merkel cell carcinomas was in the TP53 gene (12/17 patients [71%]). Abnormalities in the cell cycle pathway (CDKN2A/B, CDKN2C or RB1) were also observed in 71% of cases [12/17]. Aberrations in the PI3K/AKT/mTOR pathway (AKT2, FBXW7, NF1, PIK3CA, PIK3R1, PTEN or RICTOR) were the third most common set of aberrations (9/17 [53%]). Anomalies in DNA repair genes (ATM, BAP1, BRCA1/2, CHEK2, FANCA or MLH1) were seen in 29% (5/17) of patients. Aberrations in either ALK and RET (case 14) or ARIDIA (case 5) were each only noted in 6% (1/17) of patients.

Concurrent anomalies in both the cell cycle and PI3K/AKT/mTOR pathways were noted in 35% (6/17) of patients (cases 1, 3, 7, 10, 16 and 17). Abnormalities of both the cell cycle pathway and DNA repair genes occurred in 18% (3/17) of patients (cases 4, 9 and 12) and aberrations in PI3K/AKT/mTOR pathway and DNA repair genes were discerned in 12% (2/17) of patients (cases 13 and 15).

Number of genomic aberrations and the distinctness of the profiles (Tables 1 and 2)

There were 30 distinct genes involved with 60 distinct molecular alterations. Genomic twins refer to two or more patients that have alterations in the identical genes. Molecular twins refer to two or more patients that have alterations in the same genes and the specific alterations within the gene are also identical. There were no genomic or molecular twins in this study. Therefore, our analysis showed that each of the 17 Merkel cell carcinomas were distinct at the genomic and at the molecular level.

TP53 suppressor gene aberrations (Tables 1 and 2, Figure 1)

Genomic abnormalities in TP53 were found in 71% (12/17) of patients. However, amongst the 16 molecular aberrations, 15 were distinct; two patients (cases 9 and 17) had the same molecular abnormality: R248W. One tumor (case 13) harbored three distinct molecular TP53 abnormalities and two tumors (cases 16 and 17) harbored two distinct molecular aberrations.

Cyclin pathway aberrations (Tables 1 and 2, Figure 1)

Aberrations in cell cycle genes were observed in 71% (12/17) of patients. The most common aberration was in the RB1 tumor suppressor gene; RB1 was mutated in 10 patients. In one patient (case 9), there were two molecular aberrations in RB1. Genomic alterations in either CDKN2A/B (case 8) or CDKN2C (case 3) were each observed in one patient.

PI3K/AKT/mTOR pathway aberrations (Tables 1 and 2, Figure 1)

Genomic abnormalities in the PI3K/AKT/mTOR pathway were noted in 53% (9/17) of patients. There were 10 molecular abnormalities in these nine patients; one patient (case 13) had an aberration in both PIK3R1 and PTEN. The most common genomic aberration was in PIK3CA [found in three patients (cases 13, 15 and 16)]; two patients had a genomic aberration of the NF1 gene.

DNA repair gene aberrations (Tables 1 and 2, Figure 1)

DNA repair gene abnormalities were observed in 29% (5/17) of patients. They included eight molecular abnormalities. Two patients had genomic aberration of BAP1 (cases 4 and 9); two patients had BRCA1/2 alterations (case 13 had a BRCA1 abnormality and case 4 had a BRCA2 abnormality). In two of the five patients, there were abnormalities in multiple DNA repair genes; either BAP1 and BRCA2 (case 4) or BAP1, FANCA, and MLH1 (case 9). Genomic alterations in either ATM (case 12) or CHEK2 (case 15) were each observed in one patient.

Actionable aberrations (Tables 1, 2 and 3)

Table 3: Potential therapies for genomic aberrations in each of 17 patients with Merkel cell carcinoma [3472] [a]

Abbreviations: C, case.

[a] Many of these therapies have not been validated as effective in patients.

[b] Aberration is of uncertain clinical significance and relevance of therapeutic strategies is unknown.

[c] Aberration is an inactivating alteration and therapeutic strategies are not expected to be relevant.

Of the 30 distinct genomic aberrations, 73% (22/30) were theoretically targetable by either an off-label use of an FDA-approved drug (21/30) or an experimental drug in a clinical trial where an off-label use did not exist (1/30).

The vast majority of patients (94%, 16/17) had at least one aberration that was potentially targetable. There were between zero (case 5) and four (cases 4, 9 and 13) actionable genes affected per patient (median, two genes per patient). Potential therapies for the genomic aberrations in each of the 17 patients with Merkel cell carcinoma are summarized in Table 3 [3472].

DISCUSSION

Merkel cell carcinoma is an ultra-rare neuroendocrine cancer of the skin that most commonly presents in elderly Caucasian men [5, 73]. The pathogenesis is related not only to ultraviolet light exposure, but also to immunosuppression [5, 73]. In addition, the presence of Merkel cell polyomavirus (MCPyV) has been demonstrated in about 45% [73] to 80% [74] of the cases. Gene mutations may have a role in the etiology of Merkel cell carcinoma, particularly in patients whose tumors are Merkel cell polymavirus-negative [75]. A recent study of nine virus-negative patients showed high mutational burden (as compared to that in virus-positive patients), and alterations in TP53, RB1, PIK3CA, HRAS, PRUNE2 and NOTCH (integrative sequencing that included data from whole-exome sequencing and whole-transcriptome sequencing) [13]. Another similar study (N = 619 genes analyzed; 21 virus-negative and 13 virus-positive patients) confirmed high mutation burden and a UV-induced DNA damage signature for virus-negative patients. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or amplified cancer genes of potential clinical importance included those in the PI3K or MAPK pathway [14]. Of interest, a subset of virus-negative patients showed high PDL1, suggesting that they might respond to antiPD1 checkpoint inhibitors [15].

The prognosis for patients with Merkel cell carcinoma is poor; more than 33% of patients die from their disease and 50% of patients with advanced tumors live less than 9 months following diagnosis [76]. Of interest in this regard is that exome sequencing of Merkel cell revealed that TP53 was more common in the virus-negative group and predicted a poor survival (5-year survival in TP53 mutant versus wild-type stage I and II disease was 20% vs. 92%, respectively; P = 0.0036) [16]. In general, Merkel cell carcinoma has shown low response rates to chemotherapy [4-6] and to molecularly targeted therapies that are administered without molecular matching [32]. Thus, therapeutic options for Merkel cell carcinoma are limited. In addition, we are not aware of any reports that describe the response in Merkel cell carcinomas when genetic aberrations and therapies were matched. We therefore investigated the genomic landscape of Merkel cell carcinomas by comprehensive genomic profiling and analyzed potential pharmacologic tractability.

The most common genetic aberration among 17 patients with Merkel cell carcinoma was TP53 mutation (12/17 [71%]) (Tables 1 and 2, Figure 1). Our current study observed a markedly higher incidence of TP53 mutations than that noted in previous reports that demonstrated TP53 mutations ranging from 0% to 37% [16, 19, 20, 77, 78]. The TP53 gene is large and there are many areas that can be mutated [79]; our study used comprehensive genomic profiling that evaluated all areas of the gene; in contrast, some of the earlier reported results sequenced discrete regions of the TP53 gene and may not have identified all existing mutations. TP53 gene anomalies are generally seen in virus-negative Merkel cell cancers [16], but a limitation of our study is that viral status was not available. Finally, each of the reports of Merkel cell genomics have small numbers of patients, perhaps accounting in part for the variability in percent positive for TP53 mutations.

TP53 has proven difficult to target. MDM2 inhibitors can theoretically be used in patients with wild-type TP53. Recent data suggest that TP53 mutations result in increased levels of VEGFA, which is the target of bevacizumab [80]. Said et al. showed that bevacizumab-containing regimens were associated with longer progression-free survival when compared to non-bevacizumab-containing regimens in patients with TP53-mutated advanced solid tumors (median 11.0 versus 4.0 months (p < 0.01) [37]. Wee-1 inhibitors, which are in experimental trials, may also target TP53 [81] (Table 3 [3472]).

The cell cycle pathway (CDKN2A/B, CDKN2C or RB1 genes) was also abnormal in 71% of patients (12/17) with Merkel cell carcinomas (Tables 1 and 2, Figure 1). Aberrations in the cyclin D-cyclin-dependent kinase pathway that regulates the cell cycle restriction point is a common feature of human cancer, contributing to tumor proliferation, genomic instability and chromosomal instability [12, 82, 83]. This pathway can be altered through multiple mechanisms including increased signaling through CDK4 and CDK6 amplification, overexpression of cyclin D1, and loss of inhibitors including CDKN2A and/or CDKN2B [8487]. Regarding therapeutic implications, the cell cycle pathway is possibly targetable with CDK4/6 inhibitors such as palbociclib [56], and further investigation is warranted (Table 3 [3472]).

Mutation or loss of RB1, a tumor suppressor gene, also alters the cell cycle pathway. RB1 gene alterations in Merkel cell cancers are associated with virus-negative disease [88]. Merkel cell polyomavirus large-T antigen binds RB1 with high affinity, suppressing its anti-neoplastic function [89]. Aberration of RB1 renders tumors resistant to CDK4/6 inhibitors such as palbociclib [38]. Ten patients in our series had RB1 mutations (Tables 1 and 2, Figure 1).

Importantly, aberrations in the PI3K/AKT/mTOR pathway (AKT2, FBXW7, NF1, PIK3CA, PIK3R1, PTEN or RICTOR) were also commonly seen in Merkel cell carcinomas (9/17 [53%]) (Tables 1 and 2, Figure 1). PIK3CA is a key regulator of cell motility and chemotaxis. Aberrations in PI3KCA usually occur in tumors that do not have Merkel cell polyomavirus [24, 25].

The PI3K/AKT/mTOR pathway can be targeted by PI3K/AKT/mTOR inhibitors such as everolimus and temsirolimus, both of which are FDA-approved mTOR inhibitors [42, 43]. Since Merkel cell carcinomas—regardless of whether they are positive or negative for Merkel cell polyomavirus—show activated PI3K/AKT signaling, PI3K and dual PI3K/mTOR inhibitors may be used as potential targeted therapies, though the literature suggests that for many tumors with pathway activation, they are not effective as single agents [24, 25]. With regards to RICTOR amplification, recent studies have shown that this aberration may be targetable by investigational mTORC1/mTORC2 inhibitors such as AZD8055 and MLN0128 [3941] (Table 3 [3472]).

Several investigators have also previously shown that MAP (mitogen-activated protein) kinase-related genes—such as KRAS and BRAF—are more frequently aberrant in the presence of mutant PIK3CA, as compared with wild-type PIK3CA [90]. These genes may confer resistance to PI3K/AKT/mTOR inhibitors. Interestingly, none of our patients had KRAS or BRAF alterations.

Abnormalities in the DNA repair gene pathway (ATM, BAP1, BRCA1/2, CHEK2, FANCA or MLH1) were also observed in 29% of patients (5/17) (Tables 1 and 2, Figure 1). Drugs such as platinums, PARP inhibitors, and possibly immunotherapeutic agents can target DNA repair gene abnormalities (Table 3 [3472]). Some of these abnormalities (such as BRCA1/2 or ATM) can be germline; germline testing was not conducted in the patients included in this analysis.

Interestingly, 16/17 patients (94%) had potentially actionable aberrations (Table 1). The number of actionable genes affected per patient ranged between zero (case 5) and four (cases 4, 9 and 13), with a median of two per patient. Indeed, the majority of the genomic alterations were theoretically druggable (Tables 1 and 2). Of the 22 (73%) actionable aberrations, 21 were targetable by an FDA-approved drug (off-label) (representing 70% [21/30] of all distinct alterations). An additional one (3% [1/30]) distinct alteration (RICTOR) was targetable by an experimental drug in a clinical trial. As there are no FDA-approved targeted therapies for Merkel cell carcinoma and most conventional chemotherapy has been shown to be associated with poor clinical outcomes: therefore, matched targeted therapies based on molecular profiling merits investigation [91].

Our current study has some limitations. First, it was performed retrospectively with a relatively limited number of patients. Second, molecular analysis was done on archival tumor tissue, which was obtained at different time points in relationship to the clinical history; there was no information regarding the status of the patients, whether the tumors were primary or metastatic, the location of the tumor and the presence or absence of Merkel cell polyomavirus, or cytokeratin-20 positivity (found in most, but not all, Merkel cell cancers) [95]. However, despite these limitations, the genomic characterization of Merkel cell carcinomas has uncovered interesting and possibly clinically relevant results.

In summary, our 17 patients with Merkel cell carcinomas harbored 30 genomic alterations (median = 4 per patient) of which 60 were distinct molecular aberrations. The most common genomic aberrations in patients with Merkel cell carcinoma were in the TP53 gene and the cell cycle pathway (CDKN2A/B, CDKN2C or RB1), followed by the PI3K/AKT/mTOR pathway (AKT2, FBXW7, NF1, PIK3CA, PIK3R1, PTEN or RICTOR) and DNA repair genes (ATM, BAP1, BRCA1/2, CHEK2, FANCA or MLH1). The vast majority of patients (94%) had at least one aberration that was potentially pharmacologically tractable by an FDA-approved drug or an investigational agent in a clinical trial. Indeed, of the 30 distinct genomic aberrations, 22 (73%) were potentially actionable. These observations suggest that matching patients with appropriately targeted agents is feasible and warrants study. Finally, no two patients had an identical molecular portfolio. This result is similar to that reported in metastatic breast cancer, where 131 distinct aberrations in 57 patients with no two patients having the same molecular portfolio were recently described [9294]. Taken together, these observations suggest that customized targeted combination therapy merits investigation in patients with Merkel cell carcinoma.

MATERIALS AND METHODS

Patients

We investigated the genomic alterations of patients with Merkel cell carcinoma referred to Foundation Medicine (Cambridge, MA) for next-generation sequencing (December 2011 to April 2014 (N = 17)). Here, we report the prevalence and frequencies of these aberrations. This study was performed in accordance with University of California San Diego IRB guidelines for a de-identified database.

Tissue samples and mutational analysis

Available tissues from diagnostic and therapeutic procedures were used to assess molecular aberrations. Samples from formalin-fixed paraffin-embedded tissue were sent for targeted next-generation sequencing at Foundation Medicine (Cambridge, MA). The test sequences the entire coding sequence of 182, or more recently 236, cancer-related genes plus 47 introns from 19 genes often rearranged or altered in cancer to an average depth-of-coverage of greater than 250X (http://foundationone.com/docs/FoundationOne_tech-info-and-overview.pdf).

This method of sequencing allows for detection of copy number alterations, gene rearrangements, and somatic mutations with 99% specificity and > 99% sensitivity for base substitutions at > five mutant allele frequency and > 95% sensitivity for copy number alterations. Foundation Medicine uses a threshold of > eight copies for gene amplification. The submitting physicians provided a diagnosis of the tumor. Next-generation sequencing data were collected and interpreted by N-of-One, Inc. (Lexington, MA; www.n-of-one.com). For the purpose of our analysis, “cell cycle pathway” aberrations included CDKN2A/B, CDKN2C or RB1 alterations. Similarly, “phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway” aberrations included alterations of AKT2, FBXW7, NF1, PIK3CA, PIK3R1, PTEN or RICTOR. “DNA repair gene” abnormalities included alterations in ATM, BAP1, BRCA1/2, CHEK2, FANCA or MLH1. We have evaluated whether certain genomic alterations were actionable or not based on the availability of a drug that is approved or in clinical trials that targets that aberration with low 50% inhibitory concentration (IC50) or an antibody that primarily targets that abnormality.

ACKNOWLEDGMENTS

Philip R. Cohen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

FUNDING

This project was supported in part by the Joan and Irwin Jacobs Fund.

CONFLICTS OF INTEREST

Razelle Kurzrock has research funds from Genentech, Merck Serono, Pfizer, Guardant, Foundation Medicine, and Sequenom, consultant fees from Sequenom, and an ownership interest in Novena, Inc. Sheryl K. Elkin, Brett N. Tomson, Erica Marchlik, and Jennifer Levin Carter are employees of N-of-One, Inc., Lexington, MA. Philip R. Cohen has no conflicts.

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