ERCC1 Expression Predicts Treatment Outcome

SAN FRANCISCO – Pretreatment ex­pression of ERCC1 in localized esophageal and gastroesophageal ade­nocarcinomas is a marker for outcomes among patients given trimodality thera­py that includes oxaliplatin-based chemoradiation, investigators reported from a prospective study.

Fully 58% of the 55 patients studied from the Southwest Oncology Group (SWOG) S0356 trial had tumors ex­pressing a high level of mRNA for ERCC1, a key gene in the repair of plat­inum- and radiation-induced DNA dam­age.«http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=103&abstractID=71402»

Compared with their counterparts whose tumors had low expression, these patients were nearly three times more likely to experience progression and more than twice as likely to die, accord­ing to results reported at the meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

“ERCC1 mRNA level is a very promis­ing pretreatment biomarker in patients with localized esophageal and gastroe­sophageal adenocarcinoma treated with trimodality treatment,” asserted lead in­vestigator Dr. Pierre O. Bohanes. “Based on these and published data, the SWOG is planning a prospective biomarker-dri­ven clinical trial.”

“In contrast to the growing number of predictive biomarkers for anticancer agents, there are no established bio­markers to select patients who will ben­efit most from chemoradiation,” he noted. “Utilization of predictive bio­markers to select therapy should lead to higher cure rates.”

The phase II trial, which was largely community based, enrolled patients with clinical stage II or III esophageal or gas­troesophageal junction adenocarcinoma. They underwent tumor biopsy, then chemoradiation (oxaliplatin, 5-fluo­rouracil, and 45-Gy external beam radi­ation), then surgery, and finally more chemotherapy (oxaliplatin and 5-fluo­rouracil).

Response Genetics Inc., manufacturer of several biomarker assays, analyzed tumor ERCC1 mRNA expression for the 55 patients who had sufficient pretreatment tumor tissue. Laser-capture mi­crodissection was used to ensure that only tumor cells were analyzed.

“ERCC1 has been shown to be a crit­ical gene in DNA repair,” Dr. Bohanes explained. “ERCC1 is involved in the nucleotide excision repair pathway, which recognizes and removes platinum-induced DNA adducts.” Higher expres­
sion is associated with resistance to plat­inum compounds, including cisplatin, oxaliplatin, and carboplatin.

“Also more recently, ERCC1 has been shown to be involved in the double-strand break repair pathway, which re­pairs radiation-induced damage,” he further observed.

Tumors were classified as having a high or low level of ERCC1 expression using a cutoff mRNA level of greater than 1.7 for high expression, as estab­lished in previous studies.

The 55 patients studied had a median age of 64 years. Most were men (93%) and white (94%), and had esophageal tu­mors (62%). One-fourth of them were found to have a pathological complete response at the time of surgery.

The median duration of follow-up was 36.8 months, reported Dr. Bohanes, a re­search fellow in medical oncology at the University of Southern California in Los Angeles.

Results showed that patients having high vs. low tumor expression of ERCC1 had a nearly tripled risk of progression (hazard ratio, 2.97; P = .006).«change in ONCR rendition» The medi­an duration of progression-free survival was 14.8 months for the former but was not reached for the latter. Corresponding 2-year rates of progression-free survival were 17% and 67%.

Similarly, patients with tumors having high vs. low expression of ERCC1 had a more than doubling of the risk of death (HR, 2.32; P = .047). «change in ONCR rendition» The median dura­tion of overall survival was 22.4 months for the former but was not reached for the latter. Corresponding 2-year rates of overall survival were 37% and 72%.

Expression of ERCC1 was not associ­ated with pathological complete re­sponse. Also, expression of a host of other genes – XPD and RRM1 (associat­ed with DNA repair), GSTP1 (associated with platinum detoxification), and TS, TP, and DPD (associated with 5-fluo­rouracil metabolism) – was not associat­ed with any of the outcomes studied.

“Biomarker studies are feasible within cooperative groups,” commented Dr. Bohanes, but adequate tissue was avail­able for only 55 of 92 eligible patients. Hence, “future trials need to request ad­ditional endoscopic biopsies to allow for sufficient tumor tissue collection.”

A study shortcoming was an inability to determine whether ERCC1 expression correlates with disease stage, he ac­knowledged.

“The design of this study unfortu­nately did not require preoperative en­doscopic ultrasound because it was thought that it would have hampered the
recruitment of this trial,” he said. “And often, in the community setting, endoscopic ultrasound is not avail­able.”

Also, the study could not deter­mine whether ERCC1 expression is a prognostic marker. “We would need a control arm without platinum agent,” he noted.

<[stk 3]>“I think that the patients with high expression are not benefiting from this treatment” and should be treated with alternative treatments, commented Dr. Heinz-Josef Lenz, senior investigator and chair of the gastrointestinal oncology program at the University of Southern Cali­fornia. <[etk]>

“We have choices, and I think that would certainly be part of the new concept and design going forward, ” he added.

<[stk 3]>Dr. Lenz agreed with an attendee that recruiting patients with esophageal and gastroesophageal cancer to randomized trials has been difficult in the past and it might therefore take many years to obtain important biomarker data. But adaptive trial designs are ad­dressing this issue.<[etk]>

I have checked the following facts in my story: (Please initial each.)

Meeting: 3660-11

Drug names and dosages: SML jsm

Lab test values and their units: n/a na

Citation (e.g., JAMA 2008;299:785-92): n/a na

Investigators’ names and affiliations: SML jsm

All other proper names (e.g., clinical trials; geographic, company, and test names): SML jsm

Investigators’ conflicts of interest and sponsor of study: SML jsm

Please provide your best contact number and email for questions on this story: (206) 393-2459; [email protected]

Notes:

(1) Abstract 2; log in on main ASCO page first -- http://www.asco.org

username: gi_pressaccess

password: pre$$1

Go to Virtual Meeting. Note: search function for this meeting is not working well yet, so better to look by track.

(2) Either they did not show the conflicts of interest slides at the start of the session or they blew through them at lightspeed. I don’t have any photos of them and they are not up on the Web site. So Dr. Lenz’s conflicts come from a slide in Dr. Bohanes’ talk, where the nature of the conflicts was not given.

“I think we are incorporating now more technologies with the design, which may be more flexible to adapt new findings so that we are not stuck for the next 3 or 5 years to a trial be­cause of low accrual,” he said.

Dr. Bohanes reported that he had no relevant conflicts of interest.

Dr. Lenz reported having relation­ships with Response Genetics Inc. and with Sanofi-Aventis, manufac­turer of oxaliplatin (Eloxatin). 

SAN FRANCISCO – Pretreatment ex­pression of ERCC1 in localized esophageal and gastroesophageal ade­nocarcinomas is a marker for outcomes among patients given trimodality thera­py that includes oxaliplatin-based chemoradiation, investigators reported from a prospective study.

Fully 58% of the 55 patients studied from the Southwest Oncology Group (SWOG) S0356 trial had tumors ex­pressing a high level of mRNA for ERCC1, a key gene in the repair of plat­inum- and radiation-induced DNA dam­age.«http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=103&abstractID=71402»

Compared with their counterparts whose tumors had low expression, these patients were nearly three times more likely to experience progression and more than twice as likely to die, accord­ing to results reported at the meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

“ERCC1 mRNA level is a very promis­ing pretreatment biomarker in patients with localized esophageal and gastroe­sophageal adenocarcinoma treated with trimodality treatment,” asserted lead in­vestigator Dr. Pierre O. Bohanes. “Based on these and published data, the SWOG is planning a prospective biomarker-dri­ven clinical trial.”

“In contrast to the growing number of predictive biomarkers for anticancer agents, there are no established bio­markers to select patients who will ben­efit most from chemoradiation,” he noted. “Utilization of predictive bio­markers to select therapy should lead to higher cure rates.”

The phase II trial, which was largely community based, enrolled patients with clinical stage II or III esophageal or gas­troesophageal junction adenocarcinoma. They underwent tumor biopsy, then chemoradiation (oxaliplatin, 5-fluo­rouracil, and 45-Gy external beam radi­ation), then surgery, and finally more chemotherapy (oxaliplatin and 5-fluo­rouracil).

Response Genetics Inc., manufacturer of several biomarker assays, analyzed tumor ERCC1 mRNA expression for the 55 patients who had sufficient pretreatment tumor tissue. Laser-capture mi­crodissection was used to ensure that only tumor cells were analyzed.

“ERCC1 has been shown to be a crit­ical gene in DNA repair,” Dr. Bohanes explained. “ERCC1 is involved in the nucleotide excision repair pathway, which recognizes and removes platinum-induced DNA adducts.” Higher expres­
sion is associated with resistance to plat­inum compounds, including cisplatin, oxaliplatin, and carboplatin.

“Also more recently, ERCC1 has been shown to be involved in the double-strand break repair pathway, which re­pairs radiation-induced damage,” he further observed.

Tumors were classified as having a high or low level of ERCC1 expression using a cutoff mRNA level of greater than 1.7 for high expression, as estab­lished in previous studies.

The 55 patients studied had a median age of 64 years. Most were men (93%) and white (94%), and had esophageal tu­mors (62%). One-fourth of them were found to have a pathological complete response at the time of surgery.

The median duration of follow-up was 36.8 months, reported Dr. Bohanes, a re­search fellow in medical oncology at the University of Southern California in Los Angeles.

Results showed that patients having high vs. low tumor expression of ERCC1 had a nearly tripled risk of progression (hazard ratio, 2.97; P = .006).«change in ONCR rendition» The medi­an duration of progression-free survival was 14.8 months for the former but was not reached for the latter. Corresponding 2-year rates of progression-free survival were 17% and 67%.

Similarly, patients with tumors having high vs. low expression of ERCC1 had a more than doubling of the risk of death (HR, 2.32; P = .047). «change in ONCR rendition» The median dura­tion of overall survival was 22.4 months for the former but was not reached for the latter. Corresponding 2-year rates of overall survival were 37% and 72%.

Expression of ERCC1 was not associ­ated with pathological complete re­sponse. Also, expression of a host of other genes – XPD and RRM1 (associat­ed with DNA repair), GSTP1 (associated with platinum detoxification), and TS, TP, and DPD (associated with 5-fluo­rouracil metabolism) – was not associat­ed with any of the outcomes studied.

“Biomarker studies are feasible within cooperative groups,” commented Dr. Bohanes, but adequate tissue was avail­able for only 55 of 92 eligible patients. Hence, “future trials need to request ad­ditional endoscopic biopsies to allow for sufficient tumor tissue collection.”

A study shortcoming was an inability to determine whether ERCC1 expression correlates with disease stage, he ac­knowledged.

“The design of this study unfortu­nately did not require preoperative en­doscopic ultrasound because it was thought that it would have hampered the
recruitment of this trial,” he said. “And often, in the community setting, endoscopic ultrasound is not avail­able.”

Also, the study could not deter­mine whether ERCC1 expression is a prognostic marker. “We would need a control arm without platinum agent,” he noted.

<[stk 3]>“I think that the patients with high expression are not benefiting from this treatment” and should be treated with alternative treatments, commented Dr. Heinz-Josef Lenz, senior investigator and chair of the gastrointestinal oncology program at the University of Southern Cali­fornia. <[etk]>

“We have choices, and I think that would certainly be part of the new concept and design going forward, ” he added.

<[stk 3]>Dr. Lenz agreed with an attendee that recruiting patients with esophageal and gastroesophageal cancer to randomized trials has been difficult in the past and it might therefore take many years to obtain important biomarker data. But adaptive trial designs are ad­dressing this issue.<[etk]>

I have checked the following facts in my story: (Please initial each.)

Meeting: 3660-11

Drug names and dosages: SML jsm

Lab test values and their units: n/a na

Citation (e.g., JAMA 2008;299:785-92): n/a na

Investigators’ names and affiliations: SML jsm

All other proper names (e.g., clinical trials; geographic, company, and test names): SML jsm

Investigators’ conflicts of interest and sponsor of study: SML jsm

Please provide your best contact number and email for questions on this story: (206) 393-2459; [email protected]

Notes:

(1) Abstract 2; log in on main ASCO page first -- http://www.asco.org

username: gi_pressaccess

password: pre$$1

Go to Virtual Meeting. Note: search function for this meeting is not working well yet, so better to look by track.

(2) Either they did not show the conflicts of interest slides at the start of the session or they blew through them at lightspeed. I don’t have any photos of them and they are not up on the Web site. So Dr. Lenz’s conflicts come from a slide in Dr. Bohanes’ talk, where the nature of the conflicts was not given.

“I think we are incorporating now more technologies with the design, which may be more flexible to adapt new findings so that we are not stuck for the next 3 or 5 years to a trial be­cause of low accrual,” he said.

Dr. Bohanes reported that he had no relevant conflicts of interest.

Dr. Lenz reported having relation­ships with Response Genetics Inc. and with Sanofi-Aventis, manufac­turer of oxaliplatin (Eloxatin). 

SAN FRANCISCO – Pretreatment ex­pression of ERCC1 in localized esophageal and gastroesophageal ade­nocarcinomas is a marker for outcomes among patients given trimodality thera­py that includes oxaliplatin-based chemoradiation, investigators reported from a prospective study.

Fully 58% of the 55 patients studied from the Southwest Oncology Group (SWOG) S0356 trial had tumors ex­pressing a high level of mRNA for ERCC1, a key gene in the repair of plat­inum- and radiation-induced DNA dam­age.«http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=103&abstractID=71402»

Compared with their counterparts whose tumors had low expression, these patients were nearly three times more likely to experience progression and more than twice as likely to die, accord­ing to results reported at the meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

“ERCC1 mRNA level is a very promis­ing pretreatment biomarker in patients with localized esophageal and gastroe­sophageal adenocarcinoma treated with trimodality treatment,” asserted lead in­vestigator Dr. Pierre O. Bohanes. “Based on these and published data, the SWOG is planning a prospective biomarker-dri­ven clinical trial.”

“In contrast to the growing number of predictive biomarkers for anticancer agents, there are no established bio­markers to select patients who will ben­efit most from chemoradiation,” he noted. “Utilization of predictive bio­markers to select therapy should lead to higher cure rates.”

The phase II trial, which was largely community based, enrolled patients with clinical stage II or III esophageal or gas­troesophageal junction adenocarcinoma. They underwent tumor biopsy, then chemoradiation (oxaliplatin, 5-fluo­rouracil, and 45-Gy external beam radi­ation), then surgery, and finally more chemotherapy (oxaliplatin and 5-fluo­rouracil).

Response Genetics Inc., manufacturer of several biomarker assays, analyzed tumor ERCC1 mRNA expression for the 55 patients who had sufficient pretreatment tumor tissue. Laser-capture mi­crodissection was used to ensure that only tumor cells were analyzed.

“ERCC1 has been shown to be a crit­ical gene in DNA repair,” Dr. Bohanes explained. “ERCC1 is involved in the nucleotide excision repair pathway, which recognizes and removes platinum-induced DNA adducts.” Higher expres­
sion is associated with resistance to plat­inum compounds, including cisplatin, oxaliplatin, and carboplatin.

“Also more recently, ERCC1 has been shown to be involved in the double-strand break repair pathway, which re­pairs radiation-induced damage,” he further observed.

Tumors were classified as having a high or low level of ERCC1 expression using a cutoff mRNA level of greater than 1.7 for high expression, as estab­lished in previous studies.

The 55 patients studied had a median age of 64 years. Most were men (93%) and white (94%), and had esophageal tu­mors (62%). One-fourth of them were found to have a pathological complete response at the time of surgery.

The median duration of follow-up was 36.8 months, reported Dr. Bohanes, a re­search fellow in medical oncology at the University of Southern California in Los Angeles.

Results showed that patients having high vs. low tumor expression of ERCC1 had a nearly tripled risk of progression (hazard ratio, 2.97; P = .006).«change in ONCR rendition» The medi­an duration of progression-free survival was 14.8 months for the former but was not reached for the latter. Corresponding 2-year rates of progression-free survival were 17% and 67%.

Similarly, patients with tumors having high vs. low expression of ERCC1 had a more than doubling of the risk of death (HR, 2.32; P = .047). «change in ONCR rendition» The median dura­tion of overall survival was 22.4 months for the former but was not reached for the latter. Corresponding 2-year rates of overall survival were 37% and 72%.

Expression of ERCC1 was not associ­ated with pathological complete re­sponse. Also, expression of a host of other genes – XPD and RRM1 (associat­ed with DNA repair), GSTP1 (associated with platinum detoxification), and TS, TP, and DPD (associated with 5-fluo­rouracil metabolism) – was not associat­ed with any of the outcomes studied.

“Biomarker studies are feasible within cooperative groups,” commented Dr. Bohanes, but adequate tissue was avail­able for only 55 of 92 eligible patients. Hence, “future trials need to request ad­ditional endoscopic biopsies to allow for sufficient tumor tissue collection.”

A study shortcoming was an inability to determine whether ERCC1 expression correlates with disease stage, he ac­knowledged.

“The design of this study unfortu­nately did not require preoperative en­doscopic ultrasound because it was thought that it would have hampered the
recruitment of this trial,” he said. “And often, in the community setting, endoscopic ultrasound is not avail­able.”

Also, the study could not deter­mine whether ERCC1 expression is a prognostic marker. “We would need a control arm without platinum agent,” he noted.

<[stk 3]>“I think that the patients with high expression are not benefiting from this treatment” and should be treated with alternative treatments, commented Dr. Heinz-Josef Lenz, senior investigator and chair of the gastrointestinal oncology program at the University of Southern Cali­fornia. <[etk]>

“We have choices, and I think that would certainly be part of the new concept and design going forward, ” he added.

<[stk 3]>Dr. Lenz agreed with an attendee that recruiting patients with esophageal and gastroesophageal cancer to randomized trials has been difficult in the past and it might therefore take many years to obtain important biomarker data. But adaptive trial designs are ad­dressing this issue.<[etk]>

I have checked the following facts in my story: (Please initial each.)

Meeting: 3660-11

Drug names and dosages: SML jsm

Lab test values and their units: n/a na

Citation (e.g., JAMA 2008;299:785-92): n/a na

Investigators’ names and affiliations: SML jsm

All other proper names (e.g., clinical trials; geographic, company, and test names): SML jsm

Investigators’ conflicts of interest and sponsor of study: SML jsm

Please provide your best contact number and email for questions on this story: (206) 393-2459; [email protected]

Notes:

(1) Abstract 2; log in on main ASCO page first -- http://www.asco.org

username: gi_pressaccess

password: pre$$1

Go to Virtual Meeting. Note: search function for this meeting is not working well yet, so better to look by track.

(2) Either they did not show the conflicts of interest slides at the start of the session or they blew through them at lightspeed. I don’t have any photos of them and they are not up on the Web site. So Dr. Lenz’s conflicts come from a slide in Dr. Bohanes’ talk, where the nature of the conflicts was not given.

“I think we are incorporating now more technologies with the design, which may be more flexible to adapt new findings so that we are not stuck for the next 3 or 5 years to a trial be­cause of low accrual,” he said.

Dr. Bohanes reported that he had no relevant conflicts of interest.

Dr. Lenz reported having relation­ships with Response Genetics Inc. and with Sanofi-Aventis, manufac­turer of oxaliplatin (Eloxatin).