RU2732336C1 - Method for predicting effectiveness of neoadjuvant chemoradiotherapy in rectal adenocarcinoma - Google Patents
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Abstract
Description
Изобретение относится к области медицины, а именно к онкологии. The invention relates to medicine, namely to oncology.
На сегодняшний день неоадъювантная химиолучевая терапия используется более чем у половины пациентов с аденокарциномой прямой кишки, как первый этап лечебного воздействия. Широкие показания к этому методу лечения связаны с необходимостью создания условий для выполнения адекватного оперативного вмешательства с позиций радикальности. Несмотря на современные достижения радиотерапии, у ряда пациентов эффект от проведенного облучения в сочетании с химиотерапией, оцененный через 8 недель после завершения, оказывается недостаточным. Для этой группы больных проведение лучевой терапии лишь отодвигает сроки начала оперативного лечения, что может негативно сказаться на результатах лечения. В настоящее время существует необходимость в эффективных методах прогнозирования лечебного ответа на лучевую терапию при аденокарциномах прямой кишки. Today, neoadjuvant chemoradiation therapy is used in more than half of patients with rectal adenocarcinoma as the first stage of treatment. Wide indications for this method of treatment are associated with the need to create conditions for an adequate surgical intervention from the standpoint of radicalism. Despite the modern advances in radiotherapy, in a number of patients the effect of radiation in combination with chemotherapy, assessed 8 weeks after completion, is insufficient. For this group of patients, radiation therapy only postpones the start of surgical treatment, which may negatively affect the results of treatment. Currently, there is a need for effective methods for predicting the therapeutic response to radiation therapy for rectal adenocarcinomas.
Уровень техники.State of the art.
К настоящему времени выполнен ряд исследований, направленных на поиск прогностических маркеров эффективности неоадъювантной химиолучевой терапии при аденокарциноме прямой кишки.To date, a number of studies have been carried out aimed at finding prognostic markers of the effectiveness of neoadjuvant chemoradiation therapy in rectal adenocarcinoma.
Например исследование Spindler K.L. et al. (Spindler K.L., Nielsen J.N., Lindebjerg J. et al. Germline polymorphisms may act as predictors of response to preoperative chemoradiation in locally advanced T3 rectal tumors. Dis Colon Rectum 2007;50:1363–9.) выявило, что некоторые комбинации полиморфизмов генов EGFR, EGF, генов тимидилсинтетазы позволяют предсказать наступление полного эффекта химиолучевой терапии в 41% случаев и неполный эффект в 90% случаев.For example, a study by Spindler K.L. et al. (Spindler KL, Nielsen JN, Lindebjerg J. et al. Germline polymorphisms may act as predictors of response to preoperative chemoradiation in locally advanced T3 rectal tumors. Dis Colon Rectum 2007; 50: 1363-9.) Revealed that some combinations of gene polymorphisms EGFR, EGF, thymidyl synthetase genes allow predicting the onset of the full effect of chemoradiation therapy in 41% of cases and an incomplete effect in 90% of cases.
В своей работе Saigusa S. et al. (Saigusa S., Tanaka K., Toiyama Y. et al. Gene expression profiles of tumor regression grade in locally advanced rectal cancer after neoadjuvant chemoradiotherapy. Oncol Rep 2012;28(3):855–61. doi: 10.3892/or.2012.1863.) произвели оценку экспрессии 20 генов (PCNA, MKI67, CDKN1A (p21Cip1), CDK2, CHEK1, PDRG1, LGR5, PROM1 (CD133), CD44, SOX2, POU5F1 (OCT4), LKB1, VEGF, EGFR, HGF, MET, HIF1, GLUT1, BAX и BCL2). Исследование показало, что повышенная экспрессия генов LGR5, PDRG1, GLUT1 и MKI67, было ассоциировано с низкой степенью лечебного патоморфоза, в то время как высокая экспрессия гена bax ассоциировалась с высокой степенью лечебного патоморфоза.Saigusa S. et al. (Saigusa S., Tanaka K., Toiyama Y. et al. Gene expression profiles of tumor regression grade in locally advanced rectal cancer after neoadjuvant chemoradiotherapy. Oncol Rep 2012; 28 (3): 855-61. Doi: 10.3892 / or. 2012.1863.) Evaluated the expression of 20 genes (PCNA, MKI67, CDKN1A (p21Cip1), CDK2, CHEK1, PDRG1, LGR5, PROM1 (CD133), CD44, SOX2, POU5F1 (OCT4), LKB1, VEGF, EGFR, HGF HIF1, GLUT1, BAX and BCL2). The study showed that increased expression of genes LGR5, PDRG1, GLUT1 and MKI67 was associated with a low degree of curative pathomorphosis, while high expression of the bax gene was associated with a high degree of curative pathomorphosis.
Предлагаемое изобретение позволит прогнозировать эффективность проведения неоадъювантной химиолучевой терапии, определяемой по степени лечебного патоморфоза в опухоли по Лавниковой, пациентам с аденокарциномой прямой кишки в зависимости от носительства полиморфных аллелей генов XPD (Lis751Gln), MMP-1 (-1607 insG) и TNF (G308A). The proposed invention will make it possible to predict the effectiveness of neoadjuvant chemoradiation therapy, determined by the degree of therapeutic pathomorphosis in the tumor according to Lavnikova, in patients with rectal adenocarcinoma, depending on the carriage of polymorphic alleles of the XPD (Lis751Gln), MMP-1 (-1607 insG) and) TNF (G308) genes ...
Технический результат – возможность прогнозирования эффективности неоадъювантной химиолучевой терапии при аденокарциноме прямой кишки.The technical result is the ability to predict the effectiveness of neoadjuvant chemoradiation therapy for rectal adenocarcinoma.
Сущность изобретения.The essence of the invention.
Полиморфизм генов определяется методом выделения ДНК из лейкоцитов венозной крови с последующей её амплификацией с помощью полимеразной цепной реакции (ПЦР) с фиксацией результата путём электрофоретической детекции в агарозном геле. В результате у пациента обнаруживается носительство одного из вариантов полиморфизма: 1) гомозигота по 1 аллелю (доминантному аллелю); 2) носительство гетерозиготного сочетания; 3) гомозигота по рецессивному аллелю.Gene polymorphism is determined by isolating DNA from leukocytes of venous blood with its subsequent amplification using polymerase chain reaction (PCR) with fixing the result by electrophoretic detection in agarose gel. As a result, the patient is found to be carriage of one of the variants of polymorphism: 1) homozygote for 1 allele (dominant allele); 2) carriage of a heterozygous combination; 3) homozygote for the recessive allele.
Проанализированы результаты лечения 45 пациентов с диагнозом аденокарциномы прямой кишки, получавших неоадъювантную химиолучевую терапию. Всем пациентам проводилась неоадъювантная химиолучевая терапия - конформная дистанционная лучевая терапия в классическом режиме фракционирования (РОД=2,0 Гр) до суммарной дозы 50 Гр с радиомодификаторами фторпиримидинового ряда (5-фторурацил и капецитабин согласно рекомендованным в клинических рекомендациях схемам). В дальнейшем всем пациентам была выполнена радикальная операция. Время между окончанием химиолучевой терапии и оперативным лечением составляло 8 недель. После выполнения оперативного пособия при патогистологическом исследовании определялась степень лечебного патоморфоза по Лавниковой. Наличие III и IV степени патоморфоза, соответствующие остаточной опухолевой паренхиме не более 20% в исследуемом образце, свидетельствует о высокой эффективности проведённой химиолучевой терапии, выраженной радио- и химиочувствительности опухоли, а также коррелирует с лучшим прогнозом безрецидивной и общей выживаемости пациентов. Патоморфоз I и II степени с сохранением более 20% опухолевой паренхимы говорит о слабовыраженном лечебном эффекте химиолучевой терапии и о низкой чувствительности аденокарциномы прямой кишки к ионизирующему излучению и химиопрепаратам фторпиримидинового ряда. The results of treatment of 45 patients with a diagnosis of rectal adenocarcinoma who received neoadjuvant chemoradiotherapy were analyzed. All patients underwent neoadjuvant chemoradiotherapy - conformal external beam therapy in the classical fractionation mode (RD = 2.0 Gy) up to a total dose of 50 Gy with fluoropyrimidine-type radiomodifiers (5-fluorouracil and capecitabine according to the recommended clinical guidelines). Subsequently, all patients underwent radical surgery. The time between the end of chemoradiation therapy and surgical treatment was 8 weeks. After the execution of the operative aid during the pathological examination, the degree of therapeutic pathomorphosis according to Lavnikova was determined. The presence of III and IV degrees of pathomorphosis, corresponding to a residual tumor parenchyma of no more than 20% in the test sample, indicates a high efficiency of the performed chemoradiation therapy, pronounced radio and chemical sensitivity of the tumor, and also correlates with a better prognosis of disease-free and overall survival of patients. Pathomorphosis of I and II degrees with preservation of more than 20% of tumor parenchyma indicates a weakly expressed therapeutic effect of chemoradiation therapy and a low sensitivity of rectal adenocarcinoma to ionizing radiation and chemotherapy drugs of the fluoropyrimidine series.
Все пациенты были разделены на 2 группы в зависимости от степени лечебного патоморфоза в опухоли. Пациенты, у которых после терапии осталось до 20% паренхимы опухоли в виде отдельных очагов (что соответствует III и IV степени патоморфоза по Лавниковой), составили Группу 1 (21 случай). 24 пациента с оставшейся массой опухолевой паренхимы ≥20% (патоморфоз I и II степеней) вошли в Группу 2.All patients were divided into 2 groups depending on the degree of therapeutic pathomorphosis in the tumor. Patients who, after therapy, had up to 20% of the tumor parenchyma in the form of separate foci (which corresponds to III and IV degrees of pathomorphosis according to Lavnikova), constituted Group 1 (21 cases). 24 patients with the remaining mass of tumor parenchyma ≥20% (pathomorphosis of I and II degrees) were included in Group 2.
При анализе носительства различных генов в 1 группе пациентов достоверно преобладал генотип XPD (Lis751Gln) (Lis/Lis) (р=0,05). У пациентов, имеющих данный генотип, в среднем в 2,06 раза чаще отмечался лечебный патоморфоз III или IV степени в опухоли, чем у пациентов с другими вариантами полиморфизма XPD (Lis751Gln). Результаты представлены в таблице 1. When analyzing the carriage of various genes in group 1 of patients, the XPD genotype (Lis751Gln) (Lis / Lis) significantly prevailed (p = 0.05). Patients with this genotype, on average, 2.06 times more often observed therapeutic pathomorphosis of grade III or IV in the tumor than in patients with other variants of XPD polymorphism (Lis751Gln). The results are shown in Table 1.
Таблица 1Table 1
(n=21)Group 1
(n = 21)
(n=24)Group 2
(n = 24)
Р =0,053.84 *
P = 0.05
[1,18; 3,6]2.06 *
[1.18; 3.6]
Р=0,1522.05
P = 0.152
[0,261; 1,146]0.547
[0.261; 1.146]
Р=0,7290.119
P = 0.729
[0,628; 1,953]1.107
[0.628; 1.953]
Р=0,0962,768
P = 0.096
* - разница достоверна (р < 0,05)* - the difference is significant (p <0.05)
Носительство генотипа MMP-1 (-1607 insG) (2G/2G) также показало достоверную корреляцию с большей частотой развития лечебного патоморфоза III и IV степени (в 2,031 раза по сравнению в другими вариантами полиморфизма, р=0,0275). Однако, при наличии у пациента в генотипе хотя бы одного полиморфного аллеля 1G, наоборот в 1,92 раза увеличивалась вероятность патоморфоза лишь I или II степени (р=0,021), что является критерием неблагоприятного прогноза и низкой эффективности химио-лучевой терапии (Таблица 2). Carriage of the MMP-1 genotype (-1607 insG) (2G / 2G) also showed a significant correlation with a higher incidence of medical pathomorphosis of III and IV degrees (2.031 times compared to other variants of polymorphism, p = 0.0275). However, if a patient had at least one polymorphic allele 1G in the genotype, on the contrary, the probability of pathomorphosis of only I or II degree (p = 0.021) increased by 1.92 times, which is a criterion for an unfavorable prognosis and low efficacy of chemotherapy (Table 2 ).
Таблица 2table 2
(n=21)Group 1
(n = 21)
(n=24)Group 2
(n = 24)
Р=0,1751,836
P = 0.175
[0,333;1,243]0.643
[0.333; 1.243]
Р=0,02754.862 *
P = 0.0275
[1,054;3,913]2.031 *
[1.054; 3.913]
Р=0,0215.347 *
P = 0.021
[1,025;3,6]1.92 *
[1.025; 3.6]
[0,278;0,976]0.521 *
[0.278; 0.976]
* - разница достоверна (р < 0,05)* - the difference is significant (p <0.05)
Наибольшая прогностическая корреляция со степенью патоморфоза была получена при оценке совместного носительства генов MMP-1 (-1607 insG) и TNF (G308A). Данные гены являются взаимосвязанными и имеют ряд однонаправленных генетически кодируемых эффектов. Так, при наличии у пациентов полиморфизма TNF (G308A) (G/A) + MMP-1 (-1607 insG) (2G/2G) вероятность патоморфоза III или IV степени после терапии возрастала в 2,46 раз (р=0,0105). Результаты анализа совместного носительства генов MMP-1 (-1607 insG) и TNF (G308A) представлены в таблице 3.The highest predictive correlation with the degree of pathomorphosis was obtained when assessing the joint carriage of the MMP-1 (-1607 insG) and TNF (G308A) genes. These genes are interrelated and have a number of genetically encoded unidirectional effects. Thus, in the presence of TNF (G308A) (G / A) + MMP-1 (-1607 insG) (2G / 2G) polymorphism in patients, the probability of grade III or IV pathomorphism after therapy increased 2.46 times (p = 0.0105 ). The results of the analysis of the joint carriage of the MMP-1 (-1607 insG) and TNF (G308A) genes are presented in Table 3.
Таблица 3Table 3
(n=21)Group 1
(n = 21)
(n=24)Group2
(n = 24)
Р=0,0105
6,555 *
P = 0.0105
[1,365;4,345]2.436 *
[1.365; 4.345]
[0,23;0,732]0.411 *
[0.23; 0.732]
* - разница достоверна (р < 0,05) * - the difference is significant (p <0.05)
Таким образом, предложенный способ позволяет прогнозировать эффективность неоадъювантной химиолучевой терапии у пациентов с аденокарциномой прямой кишки на основании данных о полиморфизме генов XPD (Lis751Gln), MMP-1 (-1607 insG) и TNF (G308A). Возможно использование данного метода при решении вопроса о проведении неоадъювантной химиолучевой терапии на основании данных полиморфизма вышеописанных генов у пациента.Thus, the proposed method makes it possible to predict the effectiveness of neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma based on the data on the polymorphism of the XPD (Lis751Gln), MMP-1 (-1607 insG) and TNF (G308A) genes. It is possible to use this method when deciding whether to conduct neoadjuvant chemoradiation therapy based on the data of the polymorphism of the above-described genes in a patient.
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Non-Patent Citations (4)
| Title |
|---|
| Duldulao M. et al. Gene polymorphisms predict toxicity to neoadjuvant therapy in patients with rectal cancer, Cancer, 2013, vol.119(5), pp.1106-1112. * |
| SREEJA L. et al. Prognostic importance of DNA repair gene polymorphisms of XRCC1 Arg399Gln and XPD Lys751Gln in lung cancer patients from India, Journal of Cancer Research and Clinical Oncology, 2008, vol.134, pp.645-652. * |
| СНЕГИРЕВ А.А., ГРИГОРЕНКО А.А. Лечебный патоморфоз как показатель эффективности лечения и прогноза рака молочной железы, ДАЛЬНЕВОСТОЧНЫЙ МЕДИЦИНСКИЙ ЖУРНАЛ, 2013, N1, стр.134-137. * |
| СНЕГИРЕВ А.А., ГРИГОРЕНКО А.А. Лечебный патоморфоз как показатель эффективности лечения и прогноза рака молочной железы, ДАЛЬНЕВОСТОЧНЫЙ МЕДИЦИНСКИЙ ЖУРНАЛ, 2013, N1, стр.134-137. SREEJA L. et al. Prognostic importance of DNA repair gene polymorphisms of XRCC1 Arg399Gln and XPD Lys751Gln in lung cancer patients from India, Journal of Cancer Research and Clinical Oncology, 2008, vol.134, pp.645-652. Duldulao M. et al. Gene polymorphisms predict toxicity to neoadjuvant therapy in patients with rectal cancer, Cancer, 2013, vol.119(5), pp.1106-1112. * |
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