Clinical and morphological features of breast tumors with PIK3CA mutations in Russian patients: Observational study
- Authors: Sokolova T.N.1, Solov'eva T.I.1, Aleksakhina S.N.1,2, Janus G.A.1,2, Goryainova A.3, Gluzman M.I.4,5, Orlova R.V.4,6, Stukan A.I.3, Zukov R.A.7, Zyuzyukina A.V.7, Murunova Y.N.8, Sultanbaev A.V.9, Vorobeva E.N.10, Mikhaevich L.M.4, Pyliv V.N.11, Lysenko A.N.12, Khachmamuk Z.K.3, Kozlov A.E.13, Bakharev S.Y.14, Parsyan S.G.4, Rossokha E.I.14, Osidze L.D.4, Shumskaya I.S.15, Agaeva A.V.16, Kasmynina T.A.17, Klimenko V.V.1, Akhmetgareeva K.T.18, Vakhitova A.A.5,4, Chakhkieva M.D.19, Dmitriev V.N.20, Bakshun Y.I.21, Vasilyev A.E.22, Gasimly D.D.23, Kravchenko N.A.24, Maksimov D.A.25, Nesterova A.I.26,27, Sharvashidze I.O.4, Gadzaova C.H.28, Rakhmankulova G.G.16, Khamgokov Z.M.29, Amirkhanova I.K.14, Bembeeva L.V.4, Vladimirov V.I.30, Petrenko O..31, Ruskova N.G.32, Serikova E.L.4, Subbotina K.S.33, Tkachenko S.A.34, Chang V.L.35, Erdniev S.P.36, Barbara V.S.37, Vasilevskaya A.V.38, Mikheeva Y.V.39, Popova N.O.40, Startseva E.P.16, Fateeva A.V.41, Yukalchuk D.Y.12, Grechkina A.A.41, Musaeva K.S.42, Odintsova S.V.43, Stel'makh A.S.44, Khabibulaeva P.I.42, Khlobystina A.G.45, Shvaiko K.A.4, Basova E.A.17, Bogomolova I.A.46, Bolieva M.B.28, Goldberg V.E.40, Kibisheva M.V.29, Menshikov K.V.47, Ryazanov D.V.48, Stepanova M.L.49, Udalova Y.A.50, Shkradyuk A.V.51, Chapko Y.S.16, Shchukina A.A.52, Khabriev I.M.53, Kirtbaya D.V.54, Degtyarev A.M.54, Epkhiev A.A.28, Tyugina Y.A.12, Murachuev M.A.55, Togo A.V.1,56, Ievleva A.G.1,56, Imyanitov E.N.1,2,57
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Affiliations:
- Petrov National Research Center of Oncology
- Saint Petersburg State Pediatric Medical University
- Clinical Oncological Dispensary №1
- City Clinical Oncology Dispensary
- Saint Petersburg University
- University
- Voino-Yasenetskii Krasnoyarsk State Medical University
- Surgut District Clinical Hospital
- Republican Clinical Oncology Dispensary
- Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine
- District Clinical Hospital
- Regional Oncological Dispensary
- Regional Clinical Oncological Dispensary
- Altai Regional Oncological Dispensary
- Nizhny Novgorod Regional Clinical Oncological Dispensary
- Arkhangelsk Clinical Oncological Dispensary
- Oncological Dispensary, Birobidzhan
- Federal Scientific Clinical Center for Medical Radiology and Oncology
- Vedzizhev Republican Oncological Dispensary
- Belgorod Oncological Dispensary
- Kostroma Oncological Dispensary
- Orenburg Regional Clinical Oncological Dispensary
- Krasnoyarsk Regional Clinical Oncological Dispensary
- Regional Cancer Dispensary
- Tver Regional Clinical Oncological Dispensary
- Segal Republican Clinical Oncological Dispensary
- Kazan Federal University
- Republican Oncological Dispensary, Vladikavkaz
- Republican Oncological Dispensary, Nalchik
- Pyatigorsk Interdistrict Oncological Dispensary
- Central City Clinical Hospital
- Kostroma Regional Oncological
- Republican Oncological Dispensary, Petrozavodsk
- Kaluga Regional Clinical Oncological Dispensary
- Regional Oncological Clinical Dispensary
- Leningrad Regional Clinical Hospital
- Regional Clinical Hospital
- Moscow Regional Oncological Dispensary
- Saint Luke's Clinical Hospital
- Tomsk National Research Medical Center
- Primorsky Regional Oncological Dispensary
- Republican Oncological Dispensary, Grozny
- EuroCityClinic
- Murmansk Regional Oncological Dispensary
- City Clinical Oncology Dispensary, Saint Petersburg
- Federal Scientific and Clinical Center for Medical Radiology and Oncology
- Republican Clinical Oncological Dispensary
- Regional Clinical Oncological Dispensary, Ryazan
- Clinical Scientific and Practical Center for Specialised Types of Medical Care (Oncological)
- Oncological Dispensary, Taganrog
- Efetov Crimean Republican Oncological Clinical Dispensary
- Tula Regional Clinical Oncological Dispensary
- Republican Oncological Dispensary, Nazran
- Oncological Dispensary №2
- Republican Cancer Center
- State Pediatric Medical University
- Mechnikov North-Western State Medical University
- Issue: Vol 24, No 1 (2022)
- Pages: 12-23
- Section: CLINICAL ONCOLOGY
- Submitted: 25.04.2022
- Accepted: 25.04.2022
- Published: 30.04.2022
- URL: https://modernonco.orscience.ru/1815-1434/article/view/106754
- DOI: https://doi.org/10.26442/8151434.2022.1.201435
- ID: 106754
Cite item
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.
Full Text
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.
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 PetersburgTatyana I. Solov'eva
Petrov National Research Center of Oncology
Email: tatab0x@yandex.ru
oncologist
Russian Federation, Saint PetersburgSvetlana 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 PetersburgGrigorii 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 PetersburgAlla Goryainova
Clinical Oncological Dispensary №1
Email: mashelueva@yandex.ru
ORCID iD: 0000-0001-7127-7945
Department Head, oncologist
Russian Federation, KrasnodarMark 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 PetersburgRashida 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 PetersburgAnastasiya I. Stukan
Clinical Oncological Dispensary №1
Email: jolie86@bk.ru
ORCID iD: 0000-0002-0698-7710
Cand. Sci. (Med.), Clinical Oncological Dispensary
Russian Federation, KrasnodarRuslan 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, KrasnoyarskAlena V. Zyuzyukina
Voino-Yasenetskii Krasnoyarsk State Medical University
Email: alena-vz@mail.ru
ORCID iD: 0000-0002-6758-4800
Cand. Sci. (Med.)
Russian Federation, KrasnoyarskYulia N. Murunova
Surgut District Clinical Hospital
Email: rkodrb@yandex.ru
ORCID iD: 0000-0003-0299-980X
Cand. Sci. (Med.)
Russian Federation, SurgutAleksandr V. Sultanbaev
Republican Clinical Oncology Dispensary
Email: rkodrb@yandex.ru
ORCID iD: 0000-0003-0996-5995
Cand. Sci. (Med.)
Russian Federation, UfaElena 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, ChelyabinskLeonid M. Mikhaevich
City Clinical Oncology Dispensary
Email: 9119484518m@gmail.com
ORCID iD: 0000-0003-0029-7441
oncologist
Russian Federation, Saint PetersburgVictoria N. Pyliv
District Clinical Hospital
Email: 7777@86.ru
ORCID iD: 0000-0003-0475-0872
oncologist
Russian Federation, Khanty-MansiyskAnna N. Lysenko
Regional Oncological Dispensary
Email: anyutadoctor@yandex.ru
oncologist
Russian Federation, StavropolZarema K. Khachmamuk
Clinical Oncological Dispensary №1
Email: zarema2332@icloud.com
ORCID iD: 0000-0001-7745-4631
oncologis
Russian Federation, KrasnodarAndrey E. Kozlov
Regional Clinical Oncological Dispensary
Email: andrei.kozlov88@gmail.com
oncologist
Russian Federation, TulaSergey Y. Bakharev
Altai Regional Oncological Dispensary
Email: bachero@mail.ru
ORCID iD: 0000-0003-0429-8804
Department Head, pathologist
Russian Federation, BarnaulShahen G. Parsyan
City Clinical Oncology Dispensary
Email: parsian@yandex.ru
ORCID iD: 0000-0003-1557-3736
oncologist
Russian Federation, Saint PetersburgElena I. Rossokha
Altai Regional Oncological Dispensary
Email: rossokha_e@mail.ru
ORCID iD: 0000-0002-5303-3012
Cand. Sci. (Med.)
Russian Federation, BarnaulLeri D. Osidze
City Clinical Oncology Dispensary
Email: dlinniiparahod@gmail.com
ORCID iD: 0000-0002-2500-7730
oncologist
Russian Federation, Saint PetersburgIrina S. Shumskaya
Nizhny Novgorod Regional Clinical Oncological Dispensary
Email: medicanns@mail.ru
oncologist, Head of the chemotherapy service
Russian Federation, Nizhny NovgorodAnna V. Agaeva
Arkhangelsk Clinical Oncological Dispensary
Email: agaeva@onko29.ru
ORCID iD: 0000-0002-6121-274X
head pathological department
Russian Federation, ArkhangelskTatiana A. Kasmynina
Oncological Dispensary, Birobidzhan
Email: stretanya@yandex.ru
oncologist
Russian Federation, BirobidzhanVeronika V. Klimenko
Petrov National Research Center of Oncology
Email: veronika30081987@mail.ru
Cand. Sci. (Med.)
Russian Federation, Saint PetersburgKamila 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, DimitrovgradAlmira 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 PetersburgMadina D. Chakhkieva
Vedzizhev Republican Oncological Dispensary
Email: nurulnabi77@mail.ru
oncologist
Russian Federation, PlievoVadim N. Dmitriev
Belgorod Oncological Dispensary
Email: vadd@mail.ru
ORCID iD: 0000-0002-5523-5718
D. Sci. (Med.)
Russian Federation, BelgorodYana I. Bakshun
Kostroma Oncological Dispensary
Email: mikobacteria@gmail.com
ORCID iD: 0000-0001-8584-6299
oncologist
Russian Federation, KostromaAlexey E. Vasilyev
Orenburg Regional Clinical Oncological Dispensary
Email: orenonco.vasiliev@rambler.ru
ORCID iD: 0000-0003-0385-6798
oncologist, chemotherapist
Russian Federation, OrenburgDunya D. Gasimly
Krasnoyarsk Regional Clinical Oncological Dispensary
Email: dgasymly@gmail.com
oncologist
Russian Federation, KryzhanovskyNadezhda A. Kravchenko
Regional Cancer Dispensary
Email: n.kravchenko38@yandex.ru
oncologist
Russian Federation, IrkutskDmitriy A. Maksimov
Tver Regional Clinical Oncological Dispensary
Email: dr.maksimovda@mail.ru
oncologist
Russian Federation, TverAlfia 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; KazanIneza O. Sharvashidze
City Clinical Oncology Dispensary
Email: stretanya@yandex.ru
oncologist
Russian Federation, Saint PetersburgChristina H. Gadzaova
Republican Oncological Dispensary, Vladikavkaz
Email: stretanya@yandex.ru
oncologist
Russian Federation, Alanya, VladikavkazGalina G. Rakhmankulova
Arkhangelsk Clinical Oncological Dispensary
Email: magvai_29@mail.ru
oncologis
Russian Federation, ArkhangelskZaur M. Khamgokov
Republican Oncological Dispensary, Nalchik
Email: zaur0779@inbox.ru
oncologist
Russian Federation, NalchikIrina K. Amirkhanova
Altai Regional Oncological Dispensary
Email: kor3009@yandex.ru
Head of the polyclinic, oncologist
Russian Federation, VologdaLudmila V. Bembeeva
City Clinical Oncology Dispensary
Email: bembeevaluda@rambler.ru
ORCID iD: 0000-0003-4473-3049
oncologist
Russian Federation, Saint PetersburgVladimir I. Vladimirov
Pyatigorsk Interdistrict Oncological Dispensary
Email: vladvlad@megalog.ru
ORCID iD: 0000-0002-7375-8950
D. Sci. (Med.)
Russian Federation, PyatigorskOleg L. Petrenko
Central City Clinical Hospital
Email: Petrenko-oleg78@mail.ru
ORCID iD: 0000-0002-6482-1698
oncologist
Russian Federation, KaliningradNatalia G. Ruskova
Kostroma Regional Oncological
Email: natasha85doc@mail.ru
oncologist
Russian Federation, KostromaEkaterina L. Serikova
City Clinical Oncology Dispensary
Email: e.serikova@gkod.org
ORCID iD: 0000-0001-6933-0030
oncologist
Russian Federation, Saint PetersburgKsenia S. Subbotina
Republican Oncological Dispensary, Petrozavodsk
Email: Xenia.ksenia17.04@gmail.com
oncologist
Russian Federation, PetrozavodskSvetlana A. Tkachenko
Kaluga Regional Clinical Oncological Dispensary
Email: sv0959@mail.ru
Department Head, oncologist, Kaluga Regional Clinical Oncological Dispensary
Russian Federation, KalugaVictor L. Chang
Regional Oncological Clinical Dispensary
Email: ken_baxter@mail.ru
ORCID iD: 0000-0003-4799-2687
oncologist
Russian Federation, TambovSanal P. Erdniev
Leningrad Regional Clinical Hospital
Email: oncosanal@list.ru
oncologist, Head of the polyclinic
Russian Federation, Saint PetersburgVictoria S. Barbara
Regional Clinical Hospital
Email: barbara_vs@mail.ru
oncologist
Russian Federation, KaliningradAnna V. Vasilevskaya
Moscow Regional Oncological Dispensary
Email: Annavasilevs@rambler.ru
Department Head, oncologist
Russian Federation, BalashikhaYulia 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 PetersburgNataliya O. Popova
Tomsk National Research Medical Center
Email: popova75tomsk@mail.ru
ORCID iD: 0000-0001-5294-778X
Cand. Sci. (Med.)
Russian Federation, TomskEkaterina P. Startseva
Arkhangelsk Clinical Oncological Dispensary
Email: stretanya@yandex.ru
oncologist
Russian Federation, ArkhangelskAnastasia V. Fateeva
Primorsky Regional Oncological Dispensary
Email: ralise@bk.ru
Deputy Chief doctor, oncologist
Russian Federation, VladivostokDenis Y. Yukalchuk
Regional Oncological Dispensary
Email: dyuyu558@mail.ru
oncologis
Russian Federation, IrkutskAnna A. Grechkina
Primorsky Regional Oncological Dispensary
Email: cindercis@mail.ru
oncologis
Russian Federation, VladivostokKhedi S. Musaeva
Republican Oncological Dispensary, Grozny
Email: musaeva.onco@mail.ru
oncologist
Russian Federation, GroznySvetlana V. Odintsova
EuroCityClinic
Email: odin-svet@yandex.ru
Cand. Sci. (Med.)
Russian Federation, Saint PetersburgAlena S. Stel'makh
Murmansk Regional Oncological Dispensary
Email: stretanya@yandex.ru
oncologist
Russian Federation, MurmanskPetimat I. Khabibulaeva
Republican Oncological Dispensary, Grozny
Email: stretanya@yandex.ru
oncologist
Russian Federation, GroznyAlina G. Khlobystina
City Clinical Oncology Dispensary, Saint Petersburg
Email: stretanya@yandex.ru
oncologist
Russian Federation, GroznyKseniya A. Shvaiko
City Clinical Oncology Dispensary
Email: stretanya@yandex.ru
oncologist
Russian Federation, Saint PetersburgElena A. Basova
Oncological Dispensary, Birobidzhan
Email: stretanya@yandex.ru
oncologist
Russian Federation, BirobidzhanIrina A. Bogomolova
Federal Scientific and Clinical Center for Medical Radiology and Oncology
Email: 73bogomolova@gmail.com
Department Head, oncologist
Russian Federation, DimitrovgradMarina B. Bolieva
Republican Oncological Dispensary, Vladikavkaz
Email: marina-bolieva1985@mail.ru
D. Sci. (Med.), Prof., Tomsk National Research Medical Center
Russian Federation, Alania, VladikavkazViktor E. Goldberg
Tomsk National Research Medical Center
Email: goldbergve@mail.ru
ORCID iD: 0000-0003-4753-5283
D. Sci. (Med.), Prof.
Russian Federation, TomskMarianna V. Kibisheva
Republican Oncological Dispensary, Nalchik
Email: zareta.alix@yandex.ru
oncologis
Russian Federation, NalchikKonstantin V. Menshikov
Republican Clinical Oncological Dispensary
Email: kmenshikov80@bk.ru
ORCID iD: 0000-0003-3734-2779
Cand. Sci. (Med.)
Russian Federation, UfaDmitrii V. Ryazanov
Regional Clinical Oncological Dispensary, Ryazan
Email: stretanya@yandex.ru
oncologist
Russian Federation, RyazanMariya 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 PetersburgYana A. Udalova
Oncological Dispensary, Taganrog
Email: stretanya@yandex.ru
oncologist
Russian Federation, ТаганрогAleksandr 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, SimferopolYana S. Chapko
Arkhangelsk Clinical Oncological Dispensary
Email: stretanya@yandex.ru
oncologist
Russian Federation, ArkhangelskAnna A. Shchukina
Tula Regional Clinical Oncological Dispensary
Email: stretanya@yandex.ru
oncologist
Russian Federation, TulaIdris M. Khabriev
Republican Oncological Dispensary, Nazran
Email: oncoidris@mail.ru
oncologist
Russian Federation, NazranDmitrii V. Kirtbaya
Oncological Dispensary №2
Email: doc.valikovich@yandex.ru
oncologist
Russian Federation, SochiAlexey M. Degtyarev
Oncological Dispensary №2
Email: onko13@sochi.com
oncologist
Russian Federation, SochiAleksandr A. Epkhiev
Republican Oncological Dispensary, Vladikavkaz
Email: aalibek74@mail.ru
Department Head, Republican Oncological Dispensary
Russian Federation, Alania, VladikavkazYana A. Tyugina
Regional Oncological Dispensary
Email: iana.tiughina.90@mail.ru
oncologis
Russian Federation, IvanovoMirza A. Murachuev
Republican Cancer Center
Email: mirza_myrachyev@mail.ru
oncologist
Russian Federation, MahachkalaAleksandr V. Togo
Petrov National Research Center of Oncology; State Pediatric Medical University
Email: a_togo@mail.ru
oncologist
Russian Federation, Saint Petersburg; Saint PetersburgAglaya G. Ievleva
Petrov National Research Center of Oncology; State Pediatric Medical University
Email: stretanya@yandex.ru
oncologist
Russian Federation, Saint Petersburg; Saint PetersburgEvgenii 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 PetersburgReferences
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