Clinical and morphological features of breast tumors with PIK3CA mutations in Russian patients: Observational study

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Abstract

Background. By 2020, breast cancer (BC) has become the most frequent malignancy in the world. The most common type of BC is HR+/HER2-negative cancer,25–40% of which harbors PIK3CA mutations that affect the catalytic subunit of the PI3K protein. PIK3CA alterations are actionable, as such neoplasms can be treated with a combination of fulvestrant and the PI3K inhibitor alpelisib. As PIK3CA mutations have an extremely versatile effect on the characteristics of a tumor cell, numerous associations of PIK3CA mutations and various clinico-pathological characteristics of BC can be traced.

Aim. Our aim was to clarify the information on the frequency and spectrum of PIK3CA mutations in Russian patients with HR+/HER2- advanced BC, and to study the association of PIK3CA mutations with clinical and pathological parameters of BC.

Materials and methods. Tissue samples from 694 patients with HR+/HER2- advanced BC (mixed population of primary metastatic and relapsed tumors) who received any line of anti-cancer treatment in Dec 2020 to June 2021 in Russian Federation were analyzed by high-resolution melting, allele-specific PCR, digital droplet PCR and Sanger sequencing (exons 7,9, and 20 of the PIK3CA gene). Mutation rates in different BC subgroups were compared using the Fisher’s exact test. The age at diagnosis in patients with different PIK3CA status was compared using the Mann–Whitney U-test. The relationship between the PIK3CA status and the degree of tumor differentiation was compared using the Cochrane–Armitage test for trends. Luminal A and B BC expression subtypes were distinguished with surrogate IHC markers according to St.-Gallen recommendations (2013).

Results. Mutations were identified in 220/694 (32%) BC patients. The three most frequent missense substitutions in the PIK3CA gene (p.E542K, p.E545K, and p.H1047R) accounted for 190/220 (86%) mutations. Associations of PIK3CA mutations with luminal A subtype of BC, low proliferation index, small size of the primary tumor, and absence of signs of hereditary cancer were revealed. Associations of mutations in the kinase domain of PIK3CA (p.H1047R) with late recurrence of locally advanced BC and with non-Slavic ethnic origin of patients were found.

Conclusion. PIK3CA mutation rate of 32% confirms high prevalence of mutation in Russian population, with some differences reflecting the ethnic origin of patients.

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Background

Mutations in the PIK3CA gene encoding the PI3K kinase pll0alpha catalytic subunit are one of the most common driver events in human tumors [1, 2]. The development of products targeting the inhibition of PI3K/Akt/mTOR signaling pathway has been underway for many years; however, the researchers have only recently achieved acceptable levels of clinical efficacy and safety profile of these products [3, 4]. The approval of a combination of alpelisib, a pl 10 alpha isoform-selective PI3K inhibitor and degrader, and standard hormone therapy for the treatment of metastatic PIK3CA mutated HR+/HER2 breast cancer (BC) has become a significant success in this area. It is noteworthy that this regimen has also demonstrated a clinical effect in patients after progression on CDK4/6 inhibitor [5-7]. The incidence of PIK3CA mutations in this type of BC may exceed 40% [8]. Although the PI3K inhibitor monotherapy of HR+ HER2- BC was shown to be ineffective, it can be expected to be beneficial as part of rationally selected combinations in other BCs or in other types of tumors; e.g. in combination with antiandrogens in luminal AR+ triple-negative BC; with trastuzumab in EIER2-positive BC; with PARP inhibitors in ovarian cancer, etc. [9-11].

PIK3CA mutations affect a variety of biological parameters of tumor cells, including fats, carbohydrates, and amino acids metabolism, secreted immunocytokines, cell cycle stimulation, the formation of tolerance to polyploidy and chromosomal instability, etc. [12-14]. PIK3CA disease-promoting damages have both predictive and prognostic significance in BC; however, their significance varies in different clinical situations. While these mutations are associated with a favorable prognosis in the early stages of BC, they are associated with refractoriness to therapy and an unfavorable prognosis in metastatic HR+ and/or EIER2+ carcinomas. The prognosis for patients with metastatic PIK3CA mutated triple-negative BC is also relatively favorable [15-19].

Mutations in different fragments of the gene affect the properties of the mutant PIK3CA protein in different ways. Amino acid substitutions in the helical domain (exon 9) allow signal transmission through the RAS-MAPK molecular cascade independently of the p85 regulatory subunit of PI3K. Unlike this, proteins mutated in the kinase domain (exon 20) need interaction with p85 and do not depend on RAS [20]. The most frequent PIK3CA damages, which account for more than 60% of all mutations, are the p.E542K, p.E545K (helical domain), and p.H1047R (kinase domain) missense substitutions. These mutations can complement each other; two disease-promoting mutations in the helical and kinase domain in cis have been reported, and tumors with double mutations seem to respond better to anti-PBK therapy [8, 21]. The association of p.H1047R mutations (but not helical domain damage) with a low proportion of complete responses to anthracycline and taxane therapy in triple-negative BC has been reported, as well as HER2- positive tumor refractoriness to anti-HER2 therapy [22, 23]. Damaged helical domain demonstrates an association with well- differentiated luminal A HR+ BC and with a lobular molecular subtype [15, 24, 25]. Despite all functional differences, the predictive value of these two mutation categories in relation to alpelisib is apparently the same [5]. Unlike mutations in the PIK3CA spiral and kinase regions, damage to the PI3K C2 domain (exon 7) is less common. The clinical and biological significance of atypical helical and kinase domain mutations and of less frequent PIK3CA exon 7 mutations have not yet been fully described [8, 26, 27].

According to some studies, the frequency and structure of PIK3CA mutations in BC may have ethnic differences [28-30].

The purpose of this paper was to analyze the frequency, spectrum, and clinical and morphological associations of PIK3CA damage in Russian HR+ HER2- aBC patients.

 

Table 1. Clinical and pathological characteristics of the studied BC samples

Characteristics

PIK3CA WT (n=474)

PIK3CA MUT (n=220)

p-value (PIK3CA WT vs MUT)§

PIK3CA MUT (exon 9, n=88)

PIK3CA MUT (exon 20, n=123)

p-value (exon 9 vs exon 20 mutations)§*

Age (median, range)

55 (27-83)

56 (31-92)

 

55 (31-89)

57(31-92)

 

Histologic type

Ductal cancer (n=261)

175 (67%)

86 (33%)

0.7345 (ductal vs lobular)

33 (41%)

48 (59%)

 

Lobular cancer (n=45)

29 (64%)

16(36%)

4 (27%)

11 (73%)

0.3928

Other (n=32)

27 (84%)

5 (16%)

3 (75%)

1 (25%)

(ductal vs lobular)

ND(n=356)

243 (68%)

113 (32%)

48 (35%)

63 (65%)

 

Primary tumor size (T)**

 

 

0.0177

(T1-T2 vs T3-T4)

 

 

 

T1 (n=127)

75 (59%)

52 (41%)

22 (43%)

29 (57%)

 

T2 (n=283)

188 (66%)

95 (34%)

37 (42%)

51 (58%)

1

T3 (n=43)

37 (86%)

6(14%)

2 (33%)

4 (67%)

(T1-T2 vs T3-T4)

T4(n=139)

98 (71%)

41 (29%)

17 (43%)

23 (57%)

 

ND(n=102)

76 (75%)

26 (25%)

10(38%)

16(62%)

 

Lymph nodes involvement (N)**

 

 

0.4707

(N0 vs N1-N3)

 

 

 

N0(n=141)

92 (65%)

49 (35%)

19(38%)

30 (62%)

 

N1 (n=208)

142(68%)

66 (32%)

29 (46%)

34 (54%)

0.7361

N2(n=120)

83 (69%)

37(31%)

14(30%)

19(70%)

(N0 vs N1-N3)

N3(n=110)

75 (68%)

35 (32%)

11 (29%)

22(71%)

 

ND(n=115)

82(71%)

33 (29%)

15 (29%)

18(71%)

 

Stage**

 

 

0.1365

(l-ll vs lll-IV)

 

 

 

I (n=48)

31 (65%)

17 (35%)

4 (24%)

13(76%)

 

II (n=208)

132 (63%)

76 (33%)

35 (48%)

38 (52%)

0.7689

III (n=267)

185 (69%)

82 (31%)

31 (41%)

45 (59%)

(l-ll vs lll-IV)

IV (n=83)

59 (71%)

24 (29%)

9 (38%)

15(62%)

 

ND(n=88)

67 (76%)

21 (24%)

9 (43%)

12(57%)

 

Clinical situation at the time of the analysis

 

 

0.3342 (recurrent vs primary metastatic and progressive) 1 (DFI < or >5 years)

 

 

 

Relapse (n=543)

366 (67%)

177 (33%)

71 (42%)

97 (58%)

 

DFI<1 year (n=78)

50 (64%)

28 (36%)

13 (46%)

14 (54%)

1

DFI 1-3 years (n=131)

92 (70%)

39 (30%)

17 (46%)

20 (54%)

(recurrent vs

DFI 3-5 years (n=60)

41 (68%)

19 (32%)

7(41%)

10 (59%)

primary metastatic

DFI>5 years (n=99)

67 (68%)

32 (32%)

14 (44%)

18 (67%)

and progressive)

ND (n=175)

116 (66%)

59 (34%)

20 (36%)

35 (64%)

1.000 (DFI < or >5

Primary metastatic cancer (n=83)

59(71%)

24 (29%)

9 (38%)

15 (62%)

years)

ND(n=6)

4 (67%)

2 (33%)

0 (25%)

2(100%)

 

Endocrine resistance status***

 

 

0.7637

 

 

 

Primary resistance

83 (61%)

52 (39%)

22 (44%)

28 (56%)

0.7679

Secondary resistance

46 (67%)

23 (33%)

7 (35%)

13 (65%)

 

Sensitivity

32 (64%)

18 (36%)

8 (44%)

10 (56%)

 

Unusual relapse patterns****

 

 

0.6404 (indolent vs aggressive)

 

 

0.0425 (indolent vs

Indolent (n=28)

20 (71%)

8 (29%)

1 (13%)

7 (87%)

aggressive)

Agressive (n=74)

48 (65%)

26 (35%)

15 (58%)

11 (42%)

 

Tumor differentiation grade

 

 

0.08

(G1 vs G2 vs G3)

 

 

 

G1 (n=19)

 

 

 

 

0 2

G2 (n=160)

10 (53%)

9 (47%)

3 (33%)

6 (67%)

 

G3 (n=44)

105 (66%)

55 (34%)

25 (48%)

27 (52%)

(GI VS G2 VS G3)

ND(n=471)

33 (75%)

326 (71%)

11 (25%)

145 (29%)

7 (64%)

53 (38%)

4 (46%)

86 (62%)

 

Ki67

Low (<20%; n=171)

105 (61%)

66 (39%)

p=0.0362 (low vs high)

32 (48%)

35 (52%)

0.4933

High (>20%; n=266)

190 (71%)

76 (29%)

29 (41%)

42 (59%)

(low vs high)

ND(n=257)

1 79 (70%)

78 (30%)

27 (37%)

46 (63%)

 

Surrogate molecular subtypeA

 

 

0.0283 (A vs B)

 

 

 

Luminal A (n=130)

79 (61%)

51 (39%)

21 (54%)

28 (46%)

 

Luminal В (n=366)

261 (71%)

105 (29%)

45 (45%)

56 (55%)

(A vs B)

ND(n=198)

134 (70%)

64 (30%)

22 (36%)

39 (64%)

 

Menopausal status at diagnosis

 

 

0.8427 (pre- vs postmenopause)

 

 

 

Premenopause (n=162)

113 (70%)

49 (30%)

20 (43%)

26 (57%)

1 (pre-vs

Peri-and postmenopause (n=438)

300 (68%)

138 (32%)

57 (43%)

77 (57%)

postmenopause)

ND (n=94)

61 (65%)

33 (35%)

11 (35%)

20 (65%)

 

 

Table 1. Clinical and pathological features of BC samples. The ending

Characteristics

PIK3CA WT (n=474)

PIK3CA MUT (n=220)

p-value (PIK3CA WTvs MUT)§

PIK3CA MUT (exon 9, n=88)

PIK3CA MUT (exon 20, n=123)

p-value (exon 9 vs exon 20 mutations)§*

Metastasis sites (n=260)

 

 

0.2067

 

 

0.3657

Bones only (n=58)

34 (59%)

24(41%)

9 (39%)

14(61%)

Lungs only (n=28)

15 (54%)

13 (46%)

4(31%)

9 (69%)

Soft tissues only (n=8)

7 (87%)

1 (13%)

0 (0%)

1 (100%)

Distant lymph nodes only (n=37)

27 (73%)

10(27%)

6 (67%)

3 (33%)

Liver only (n=22)

17 (77%)

5 (23%)

3 (75%)

1 (25%)

Other (n=5)

3 (60%)

2 (40%)

1 (50%)

1 (50%)

Multiple sites (n=89)

62 (70%)

27 (30%)

10(40%)

15 (60%)

Metastasis sites number

 

 

1 (>3vs 1-3)

 

 

1 (>3vs 1-3)

1-3 (n=231)

152 (66%)

79 (34%)

34 (43%)

45 (67%)

>3 (n=7)

5 (71%)

2 (29%)

1 (50%)

1 (50%)

Predictors of hereditary cancer (young age <45, multiple tumors. family history)

 

 

0.0218

 

 

0.2687

Yes (n=215)

160 (74%)

55 (26%)

26 (48%)

28 (52%)

No or ND (n=479)

314(66%)

165 (34%)

62 (39%)

95 (61%)

Ethnicity

 

 

0.1048

 

 

0.0165

Patients from the territories of the Russian Federation with Slavic population

400 (68%)

190(32%)

79 (44%)

102 (56%)

predominating (n=590) Patients from the

55 (77%)

16(23%)

2 (12%)

14(88%)

territories of the

Russian Federation with

 

 

 

 

non-Slavic population predominating#(n=71) A) North Caucasian

20 (83%)

4 (17%)

0 (0%)

4(100%)

Republics (n=24) B) Bashkortostan.

35 (74%)

12 (26%)

2 (17%)

10(83%)

Tatarstan (n=47)

ND (n=33)

19(58%)

14(42%)

7 (50%)

7 (50%)

Note. DFI - disease-free interval, ND - no data, WT - tumors without mutations, MUT - tumors with mutations; §the table shows the family-wise p-values, *nine cases of atypical and double PIK3CA mutations were excluded from the analysis, **in the case of bilateral BC, the source of the sample for genotyping was indicated where possible; the greater of the two degrees T, N, the stage was indicated where impossible, * * *primary resistance: relapse while on the first 2 years of adjuvant ET; secondary resistance - relapse while on adjuvant ET but after the first 2 years, or relapse within 12 months of completing adjuvant ET; endocrine sensitivity - relapse at least 12 months after the completion of adjuvant endocrine therapy, ****the indolent pattern of relapse is a situation when a stage III tumor recurs after 5 years; the aggressive pattern is an early (<3 years) relapse of stage l-ll tumors, distinction between expression subtypes of receptor-positive HER2-negative BC, luminal A, and В was performed with surrogate IHC markers according to St.-Gallen 2013 [37]: luminal B: Ki-67>/=20 and/or low expression of PgR, high expression of ER, #the study included patients from the following territories of the Russian Federation where the non-Slavic population predominates (according to the All-Russian Census of 2010)1: Bashkortostan (n=40), Ingushetia (n=8),Tatarstan (n=7), Chechen Republic (n=6), North Ossetia-Alania (n=5), Kabardino-Balkaria (n=4).

'Federal State Statistics Service. Available at: https://rosstat.gov.ru/vpn_popul/ Accessed: 25.03.2022.

 

Materials and methods

The study included 694 cases of HR+ HER2- aBC treated in more than 50 cities of Russia. We described some of the cases mentioned (n=206) previously [31]. Clinical and morphological characteristics of the patients are presented in table 1. Genotyping protocols were the same [31]. Briefly, after microdissection of archival tumor tissue samples and isolation of nucleic acids, fragments of the PIK3CA exons 7, 9, and 20 with mutant hotspots were studied using high resolution melting analysis of PCR amplicons (HRMA). The most frequent PIK3CA molecular defects (p.E542K, p.E545K, p.H1047R, p.H1047L, p.H1047Y) were analyzed using allele-specific PCR (AS-PCR). If melting curves deviated outside the ranges of the five mutation types detected by AS-PCR, Sanger sequencing was performed. Digital droplet PCR (ddPCR) was used to verify the borderline AS-PCR results.

Mutation rates in different BC subgroups were compared using the exact Fisher’s test. The age at diagnosis of primary tumor in patients with different PIK3CA status was compared using the Mann-Whitney U-test. The relationship between the PIK3CA status and the degree of tumor differentiation was compared using the Cochrane-Armitage test for trends.

Results

PIK3CA mutations were detected in 220/694 (32%) of HR+/HER2- BCs. The three most frequent mutations accounted for 190/220 (86%) cases: p. E542K (38/220, 17%), p.E545K (40/220, 8%), H1047R (112/220, 51%). Three more mutations were observed more than once: p.H1047L (8/220,4%), p.Q546K (5/220, 2%), and p.C420R (3/220, 13%); other mutations were detected in individual cases. In total, 4 mutations were detected in PIK3CA exon 7, 88 mutations were detected in exon 9 and 123 mutations were detected in exon 20. In addition, five double mutations were found (see table 2).

 

Table 2. Identified mutations in the PIK3CA gene

Mutation

Number of cases

Exon 7 (n=4)

C420R

3/220(1.3%)

L422W

1/220 (0.5%)

Exon 9 (n=88)

E542K

38/220(17%)

E542A

1/220 (0.5%)

E545K

40/220(18%)

E545Q

1/220 (0.5%)

E545G

1/220 (0.5%)

Q546K

5/220 (2.3%)

Q546P

1/220 (0.5%)

Q546R

1/220 (0.5%)

Exon 20 (n=123)

H1047R

112/220 (50.9%)

H1047L

8/220 (3.6%)

H1047Q

1/220 (0.5%)

H1047Y

1/220 (0.5%)

H1047L

1/220 (0.5%)

Double mutations (n=S)

H1047R+E418K

1/220 (0.5%)

G1049R+C420R

1/220 (0.5%)

H1047R+C420R

1/220 (0.5%)

M1043V+N1044Y

1/220 (0.5%)

E545Q+H1047R

1/220 (0.5%)

 

Table 1 demonstrates the results of the analysis of associations between PIK3CA mutations and their location (helical or kinase domain) and BC clinical and morphological features. PIK3CA mutations were less frequently observed in patients with a large primary tumor (>5 cm, T3 involving neighboring anatomical structures, T4), 147/410 (36%) vs 47/182 (26%); p=0.0177. PIK3CA mutations were more common in luminal A subtype vs luminal B, (51/130 (39%) vs 105/366 (29%), respectively; p=0.0283), and in tumors with a low vs high proliferation index, 66/171 (39%) vs 76/266 (29%); p=0.0362. We observed a tendency of an increased percentage of PIK3CA-mutant tumors in more highly differentiated BCs,/>=0.08. Assessing relapsing, we compared the spreading of PIK3CA mutations in late-relapsed initially local BCs (“indolent”) and early-relapsed localized tumors (“aggressive”). PIK3CA kinase domain mutations were associated with late relapses of local tumors, i.e. with indolent BCs, 7/8 (88%) vs 11/26 (42%); p=0.0425. Tumors from patients with predictors of cancer hereditary syndrome (young age, <45), multiple primary tumors, family history of BC or ovarian cancer) were found to have fewer PIK3CA positive cases 55/215 (26%) vs 165/479 (34%); p=0.0218. Finally, the samples received from the national republics where non-Slavic ethnic groups (Republic in the North Caucasus, Tatarstan, Bashkortostan) dominated showed the lower percentage of РЖЗСA-positive neoplasm compared to samples from the regions, populated mostly by Slavs: 16/71 (23%) vs 190/590 (32%) (p=0.1048). The distribution of mutation types among PIK3CA-positive BCs was also different in these categories of patients, with the predominance of kinase domain mutations in presumably non-Slavic patients. 102/181 (56%) vs 14/16 (88%), p=0.0165.

Discussion

The study analyzed a large cohort of Russian patients with HR+/HER2- aBC who received any line of anti-cancer therapy in Dec 2020 to June 2021. In general, the percentage and structure of the detected mutations correspond to the world data [8, 32]. The detected frequency of PIK3CA mutations (32%) was numerically lower than in some large multicenter studies, for example, in the work by P. Rajadurai et al., 2021 (808/1995, 41%) [33]. This difference may be attributed to the distinct distribution of transcriptional BC subtypes: for example, in the TCGA cohort, the frequency of PIK3CA mutations reached 45% in luminal A cancers (n=225), and was only 29% in luminal В tumors (n=126). We determined the transcriptional subtypes by surrogate IHC markers and also noted a significant difference between luminal A (51/130, 39%) and luminal В (105/366, 29%) carcinomas (/>=0.028). At the same time, the proportion of luminal A tumors in our cohort was somewhat low (130/596,22%) if compared to a large European study (4036/9415,43%) [34].

Interestingly, although no specific clinical features of the PIK3CA status in receptor-positive BCs were observed in Russian patients in general, the observed trend towards a lower percentage of PIK3CA-associated tumors and the predominance of kinase domain mutations in presumably non-Slavic patients (Tatars, Bashkirs, and especially North Caucasian representatives). Similar interethnic differences in the percentage of PIK3CA mutations, the nature of which remains unknown, occur, for example, between European and African-American descents in the US [28, 29].

A number of the associations we found confirmed previously published data; e.g. the association of PIK3CA mutations and a low proliferative index, luminal В subtype, and a high differentiation have been repeatedly reported [8]. As for the evidence of the association of PIK3CA mutations with the size of the primary tumor, it is quite contradictory; an association with large tumors and a connection of PIK3CA helical domain damage with the small size of the primary focus has been reported [25, 35]. The reported association between the presence of PIK3CA mutations and the late relapse of large local BCs is interesting. It can be noted that some authors explain the favorable prognostic role of PIK3CA mutations in the early stages of BC by the high expression of immune-stimulating cytokines by such tumors and pronounced infiltration by CD8+ lymphocytes [19, 36]. It is possible that the long-term asymptomatic persistence of micrometastatic foci consisting of PIK3CA-positive tumor cells is caused by their relatively high immunogenicity.

We have revealed a low percentage of PIK3CA mutations among BCs with predictors of hereditary cancer, which included young age, multiple primary tumors, or cancer in family history. At least one of these predictors was present in 215/694 (31%) cases. Obviously, the percentage of “true” monogenic tumor syndromes is small in this group, especially considering that the BRCAl-associated hereditary BCs, the most frequent in Russia, is usually a triple-negative cancer subtype which was excluded from our study.

It should be noted in conclusion that some of the results of our study, including the possible interethnic differences in the structure of PIK3CA mutations in BC, deserve further investigation.

Disclosure of Interest. The authors declare that they have no competing interests.

Authors’ contribution. The authors declare the compliance of their authorship according to the international ICMJE criteria. All authors made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, final approval of the version to be published and agree to be accountable for all aspects of the work.

Funding source. This study was supported by Novartis. During the preparation of the manuscript, the authors maintained their independence of opinion.

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About the authors

Tatyana N. Sokolova

Petrov National Research Center of Oncology

Email: stretanya@yandex.ru
ORCID iD: 0000-0002-0537-7478

Oncologist

Russian Federation, Saint Petersburg

Tatyana I. Solov'eva

Petrov National Research Center of Oncology

Email: tatab0x@yandex.ru

oncologist

Russian Federation, Saint Petersburg

Svetlana N. Aleksakhina

Petrov National Research Center of Oncology; Saint Petersburg State Pediatric Medical University

Email: abyshevasv@gmail.com
ORCID iD: 0000-0002-2149-7728

oncologist

Russian Federation, Saint Petersburg; Saint Petersburg

Grigorii A. Janus

Petrov National Research Center of Oncology; Saint Petersburg State Pediatric Medical University

Email: octavedoctor@yandex.ru
ORCID iD: 0000-0002-9844-4536

oncologist

Russian Federation, Saint Petersburg; Saint Petersburg

Alla Goryainova

Clinical Oncological Dispensary №1

Email: mashelueva@yandex.ru
ORCID iD: 0000-0001-7127-7945

Department Head, oncologist

Russian Federation, Krasnodar

Mark I. Gluzman

City Clinical Oncology Dispensary; Saint Petersburg University

Email: lok2008@list.ru
ORCID iD: 0000-0002-8965-8364

oncologist, Assoc. cafe oncology medical faculty

Russian Federation, Saint Petersburg; Saint Petersburg

Rashida V. Orlova

City Clinical Oncology Dispensary; University

Email: orlova_rashida@mail.ru
ORCID iD: 0000-0003-4447-9458

D. Sci. (Med.), Prof., City Clinical Oncology Dispensary

Russian Federation, Saint Petersburg; Saint Petersburg

Anastasiya I. Stukan

Clinical Oncological Dispensary №1

Email: jolie86@bk.ru
ORCID iD: 0000-0002-0698-7710

Cand. Sci. (Med.), Clinical Oncological Dispensary

Russian Federation, Krasnodar

Ruslan A. Zukov

Voino-Yasenetskii Krasnoyarsk State Medical University

Email: zukov_rus@mail.ru
ORCID iD: 0000-0002-7210-3020

D. Sci. (Med.), Prof.

Russian Federation, Krasnoyarsk

Alena V. Zyuzyukina

Voino-Yasenetskii Krasnoyarsk State Medical University

Email: alena-vz@mail.ru
ORCID iD: 0000-0002-6758-4800

Cand. Sci. (Med.)

Russian Federation, Krasnoyarsk

Yulia N. Murunova

Surgut District Clinical Hospital

Email: rkodrb@yandex.ru
ORCID iD: 0000-0003-0299-980X

Cand. Sci. (Med.)

Russian Federation, Surgut

Aleksandr V. Sultanbaev

Republican Clinical Oncology Dispensary

Email: rkodrb@yandex.ru
ORCID iD: 0000-0003-0996-5995

Cand. Sci. (Med.)

Russian Federation, Ufa

Elena N. Vorobeva

Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine

Email: vorobeva.elena.doc@mail.ru
ORCID iD: 0000-0003-2317-9691

oncologist

Russian Federation, Chelyabinsk

Leonid M. Mikhaevich

City Clinical Oncology Dispensary

Email: 9119484518m@gmail.com
ORCID iD: 0000-0003-0029-7441

oncologist

Russian Federation, Saint Petersburg

Victoria N. Pyliv

District Clinical Hospital

Email: 7777@86.ru
ORCID iD: 0000-0003-0475-0872

oncologist

Russian Federation, Khanty-Mansiysk

Anna N. Lysenko

Regional Oncological Dispensary

Email: anyutadoctor@yandex.ru

oncologist

Russian Federation, Stavropol

Zarema K. Khachmamuk

Clinical Oncological Dispensary №1

Email: zarema2332@icloud.com
ORCID iD: 0000-0001-7745-4631

oncologis

Russian Federation, Krasnodar

Andrey E. Kozlov

Regional Clinical Oncological Dispensary

Email: andrei.kozlov88@gmail.com

oncologist

Russian Federation, Tula

Sergey Y. Bakharev

Altai Regional Oncological Dispensary

Email: bachero@mail.ru
ORCID iD: 0000-0003-0429-8804

Department Head, pathologist

Russian Federation, Barnaul

Shahen G. Parsyan

City Clinical Oncology Dispensary

Email: parsian@yandex.ru
ORCID iD: 0000-0003-1557-3736

oncologist

Russian Federation, Saint Petersburg

Elena I. Rossokha

Altai Regional Oncological Dispensary

Email: rossokha_e@mail.ru
ORCID iD: 0000-0002-5303-3012

Cand. Sci. (Med.)

Russian Federation, Barnaul

Leri D. Osidze

City Clinical Oncology Dispensary

Email: dlinniiparahod@gmail.com
ORCID iD: 0000-0002-2500-7730

oncologist

Russian Federation, Saint Petersburg

Irina S. Shumskaya

Nizhny Novgorod Regional Clinical Oncological Dispensary

Email: medicanns@mail.ru

oncologist, Head of the chemotherapy service

Russian Federation, Nizhny Novgorod

Anna V. Agaeva

Arkhangelsk Clinical Oncological Dispensary

Email: agaeva@onko29.ru
ORCID iD: 0000-0002-6121-274X

head pathological department

Russian Federation, Arkhangelsk

Tatiana A. Kasmynina

Oncological Dispensary, Birobidzhan

Email: stretanya@yandex.ru

oncologist

Russian Federation, Birobidzhan

Veronika V. Klimenko

Petrov National Research Center of Oncology

Email: veronika30081987@mail.ru

Cand. Sci. (Med.)

Russian Federation, Saint Petersburg

Kamila T. Akhmetgareeva

Federal Scientific Clinical Center for Medical Radiology and Oncology

Email: dr.camilaakhmetgareeva@gmail.com
ORCID iD: 0000-0003-0773-1239

oncologist

Russian Federation, Dimitrovgrad

Almira A. Vakhitova

Saint Petersburg University; City Clinical Oncology Dispensary

Email: alberdovna@mail.ru
ORCID iD: 0000-0003-1321-3657

Graduate Student

Russian Federation, Saint Petersburg; Saint Petersburg

Madina D. Chakhkieva

Vedzizhev Republican Oncological Dispensary

Email: nurulnabi77@mail.ru

oncologist

Russian Federation, Plievo

Vadim N. Dmitriev

Belgorod Oncological Dispensary

Email: vadd@mail.ru
ORCID iD: 0000-0002-5523-5718

D. Sci. (Med.)

Russian Federation, Belgorod

Yana I. Bakshun

Kostroma Oncological Dispensary

Email: mikobacteria@gmail.com
ORCID iD: 0000-0001-8584-6299

oncologist

Russian Federation, Kostroma

Alexey E. Vasilyev

Orenburg Regional Clinical Oncological Dispensary

Email: orenonco.vasiliev@rambler.ru
ORCID iD: 0000-0003-0385-6798

oncologist, chemotherapist

Russian Federation, Orenburg

Dunya D. Gasimly

Krasnoyarsk Regional Clinical Oncological Dispensary

Email: dgasymly@gmail.com

oncologist

Russian Federation, Kryzhanovsky

Nadezhda A. Kravchenko

Regional Cancer Dispensary

Email: n.kravchenko38@yandex.ru

oncologist

Russian Federation, Irkutsk

Dmitriy A. Maksimov

Tver Regional Clinical Oncological Dispensary

Email: dr.maksimovda@mail.ru

oncologist

Russian Federation, Tver

Alfia I. Nesterova

Segal Republican Clinical Oncological Dispensary; Kazan Federal University

Email: haalfy@mail.ru
ORCID iD: 0000-0002-4880-4353

Cand. Sci. (Med.), Segal Republican Clinical Oncological Dispensary

Russian Federation, Kazan; Kazan

Ineza O. Sharvashidze

City Clinical Oncology Dispensary

Email: stretanya@yandex.ru

oncologist

Russian Federation, Saint Petersburg

Christina H. Gadzaova

Republican Oncological Dispensary, Vladikavkaz

Email: stretanya@yandex.ru

oncologist

Russian Federation, Alanya, Vladikavkaz

Galina G. Rakhmankulova

Arkhangelsk Clinical Oncological Dispensary

Email: magvai_29@mail.ru

oncologis

Russian Federation, Arkhangelsk

Zaur M. Khamgokov

Republican Oncological Dispensary, Nalchik

Email: zaur0779@inbox.ru

oncologist

Russian Federation, Nalchik

Irina K. Amirkhanova

Altai Regional Oncological Dispensary

Email: kor3009@yandex.ru

Head of the polyclinic, oncologist

Russian Federation, Vologda

Ludmila V. Bembeeva

City Clinical Oncology Dispensary

Email: bembeevaluda@rambler.ru
ORCID iD: 0000-0003-4473-3049

oncologist

Russian Federation, Saint Petersburg

Vladimir I. Vladimirov

Pyatigorsk Interdistrict Oncological Dispensary

Email: vladvlad@megalog.ru
ORCID iD: 0000-0002-7375-8950

D. Sci. (Med.)

Russian Federation, Pyatigorsk

Oleg L. Petrenko

Central City Clinical Hospital

Email: Petrenko-oleg78@mail.ru
ORCID iD: 0000-0002-6482-1698

oncologist

Russian Federation, Kaliningrad

Natalia G. Ruskova

Kostroma Regional Oncological

Email: natasha85doc@mail.ru

oncologist

Russian Federation, Kostroma

Ekaterina L. Serikova

City Clinical Oncology Dispensary

Email: e.serikova@gkod.org
ORCID iD: 0000-0001-6933-0030

oncologist

Russian Federation, Saint Petersburg

Ksenia S. Subbotina

Republican Oncological Dispensary, Petrozavodsk

Email: Xenia.ksenia17.04@gmail.com

oncologist

Russian Federation, Petrozavodsk

Svetlana A. Tkachenko

Kaluga Regional Clinical Oncological Dispensary

Email: sv0959@mail.ru

Department Head, oncologist, Kaluga Regional Clinical Oncological Dispensary

Russian Federation, Kaluga

Victor L. Chang

Regional Oncological Clinical Dispensary

Email: ken_baxter@mail.ru
ORCID iD: 0000-0003-4799-2687

oncologist

Russian Federation, Tambov

Sanal P. Erdniev

Leningrad Regional Clinical Hospital

Email: oncosanal@list.ru

oncologist, Head of the polyclinic

Russian Federation, Saint Petersburg

Victoria S. Barbara

Regional Clinical Hospital

Email: barbara_vs@mail.ru

oncologist

Russian Federation, Kaliningrad

Anna V. Vasilevskaya

Moscow Regional Oncological Dispensary

Email: Annavasilevs@rambler.ru

Department Head, oncologist

Russian Federation, Balashikha

Yulia V. Mikheeva

Saint Luke's Clinical Hospital

Email: yuliya.mikheeva64@gmail.com

Cand. Sci. (Med.), Clinic of High Medical Technologies named after N.I. Pirogova, oncologist, head. oncology department

Russian Federation, Saint Petersburg

Nataliya O. Popova

Tomsk National Research Medical Center

Email: popova75tomsk@mail.ru
ORCID iD: 0000-0001-5294-778X

Cand. Sci. (Med.)

Russian Federation, Tomsk

Ekaterina P. Startseva

Arkhangelsk Clinical Oncological Dispensary

Email: stretanya@yandex.ru

oncologist

Russian Federation, Arkhangelsk

Anastasia V. Fateeva

Primorsky Regional Oncological Dispensary

Email: ralise@bk.ru

Deputy Chief doctor, oncologist

Russian Federation, Vladivostok

Denis Y. Yukalchuk

Regional Oncological Dispensary

Email: dyuyu558@mail.ru

oncologis

Russian Federation, Irkutsk

Anna A. Grechkina

Primorsky Regional Oncological Dispensary

Email: cindercis@mail.ru

oncologis

Russian Federation, Vladivostok

Khedi S. Musaeva

Republican Oncological Dispensary, Grozny

Email: musaeva.onco@mail.ru

oncologist

Russian Federation, Grozny

Svetlana V. Odintsova

EuroCityClinic

Email: odin-svet@yandex.ru

Cand. Sci. (Med.)

Russian Federation, Saint Petersburg

Alena S. Stel'makh

Murmansk Regional Oncological Dispensary

Email: stretanya@yandex.ru

oncologist

Russian Federation, Murmansk

Petimat I. Khabibulaeva

Republican Oncological Dispensary, Grozny

Email: stretanya@yandex.ru

oncologist

Russian Federation, Grozny

Alina G. Khlobystina

City Clinical Oncology Dispensary, Saint Petersburg

Email: stretanya@yandex.ru

oncologist

Russian Federation, Grozny

Kseniya A. Shvaiko

City Clinical Oncology Dispensary

Email: stretanya@yandex.ru

oncologist

Russian Federation, Saint Petersburg

Elena A. Basova

Oncological Dispensary, Birobidzhan

Email: stretanya@yandex.ru

oncologist

Russian Federation, Birobidzhan

Irina A. Bogomolova

Federal Scientific and Clinical Center for Medical Radiology and Oncology

Email: 73bogomolova@gmail.com

Department Head, oncologist

Russian Federation, Dimitrovgrad

Marina B. Bolieva

Republican Oncological Dispensary, Vladikavkaz

Email: marina-bolieva1985@mail.ru

D. Sci. (Med.), Prof., Tomsk National Research Medical Center

Russian Federation, Alania, Vladikavkaz

Viktor E. Goldberg

Tomsk National Research Medical Center

Email: goldbergve@mail.ru
ORCID iD: 0000-0003-4753-5283

D. Sci. (Med.), Prof.

Russian Federation, Tomsk

Marianna V. Kibisheva

Republican Oncological Dispensary, Nalchik

Email: zareta.alix@yandex.ru

oncologis

Russian Federation, Nalchik

Konstantin V. Menshikov

Republican Clinical Oncological Dispensary

Email: kmenshikov80@bk.ru
ORCID iD: 0000-0003-3734-2779

Cand. Sci. (Med.)

Russian Federation, Ufa

Dmitrii V. Ryazanov

Regional Clinical Oncological Dispensary, Ryazan

Email: stretanya@yandex.ru

oncologist

Russian Federation, Ryazan

Mariya L. Stepanova

Clinical Scientific and Practical Center for Specialised Types of Medical Care (Oncological)

Email: Stepanova100992@mail.ru
ORCID iD: 0000-0001-5331-1206

oncologis

Russian Federation, Saint Petersburg

Yana A. Udalova

Oncological Dispensary, Taganrog

Email: stretanya@yandex.ru

oncologist

Russian Federation, Таганрог

Aleksandr V. Shkradyuk

Efetov Crimean Republican Oncological Clinical Dispensary

Email: stretanya@yandex.ru

Deputy Chief doctor, Efetov Crimean Republican Oncological Clinical Dispensary, chief non-staff oncologist

Russian Federation, Simferopol

Yana S. Chapko

Arkhangelsk Clinical Oncological Dispensary

Email: stretanya@yandex.ru

oncologist

Russian Federation, Arkhangelsk

Anna A. Shchukina

Tula Regional Clinical Oncological Dispensary

Email: stretanya@yandex.ru

oncologist

Russian Federation, Tula

Idris M. Khabriev

Republican Oncological Dispensary, Nazran

Email: oncoidris@mail.ru

oncologist

Russian Federation, Nazran

Dmitrii V. Kirtbaya

Oncological Dispensary №2

Email: doc.valikovich@yandex.ru

oncologist

Russian Federation, Sochi

Alexey M. Degtyarev

Oncological Dispensary №2

Email: onko13@sochi.com

oncologist

Russian Federation, Sochi

Aleksandr A. Epkhiev

Republican Oncological Dispensary, Vladikavkaz

Email: aalibek74@mail.ru

Department Head, Republican Oncological Dispensary

Russian Federation, Alania, Vladikavkaz

Yana A. Tyugina

Regional Oncological Dispensary

Email: iana.tiughina.90@mail.ru

oncologis

Russian Federation, Ivanovo

Mirza A. Murachuev

Republican Cancer Center

Email: mirza_myrachyev@mail.ru

oncologist

Russian Federation, Mahachkala

Aleksandr V. Togo

Petrov National Research Center of Oncology; State Pediatric Medical University

Email: a_togo@mail.ru

oncologist

Russian Federation, Saint Petersburg; Saint Petersburg

Aglaya G. Ievleva

Petrov National Research Center of Oncology; State Pediatric Medical University

Email: stretanya@yandex.ru

oncologist

Russian Federation, Saint Petersburg; Saint Petersburg

Evgenii N. Imyanitov

Petrov National Research Center of Oncology; Saint Petersburg State Pediatric Medical University; Mechnikov North-Western State Medical University

Author for correspondence.
Email: evgeny@imyanitov.spb.ru
ORCID iD: 0000-0003-4529-7891

D. Sci. (Med.), Prof., Corr. Memb. RAS

Russian Federation, Saint Petersburg; Saint Petersburg; Saint Petersburg

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