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.

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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