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short review memo https://doi.org/10.1007/s12254-021-00792-4 Molecular proﬁling leading to personalized treatment in breast cancer Eva Valentina Klocker · Marija Balic · Günther Steger Received: 6 October 2021 / Accepted: 16 December 2021 © The Author(s) 2022 Summary With the development of various targeted ment, molecular proﬁling for already established therapies in breast cancer, detection of biomarkers for biomarkers is needed. Various technologies have predicting treatment efﬁcacy gains importance. With been established, covering a wide range of recog- the deﬁnition of intrinsic subtypes, breast cancer has nized targets along with potential further biomarkers, paved the way for personalized treatment. Already such as next generation sequencing (NGS) or ribonu- known and recently recognized targets play an im- cleic acid(RNA)-based proﬁling or analyzing speciﬁc portant role both in metastatic and early breast can- targets with polymerase chain reaction (PCR) based cer. As a result, early molecular proﬁling is becoming assays. In addition, well-preserved tumor tissue for a part of early diagnostic work-up. Notwithstanding, testing is important. Deﬁning treatment targets en- further treatment targets and agents are needed, par- ables the administration of efﬁcient agents beyond ticularly in the most aggressive subtype encompassing chemotherapy. heterogenous diseases under the group of triple neg- ative breast cancer. Intrinsic subtypes and role of prognostic tests Keywords Molecular signature ·Targeted therapy · The classical stratiﬁcation into the four subgroups lu- Biomarkers · Breast cancer · Next generation minal A, luminal B, human epidermal growth factor sequencing receptor 2 positive (HER2+) and triple negative is still crucial in the treatment of breast cancer. In addi- tion to deﬁnition of the subtype, in hormone receptor Breast cancer is the most common tumor in women positive (HR+), HER2– BC the estimation of risk for re- and the second most common cause for cancer-re- currence is important for treatment decisions. Several lated death in women . During the last decades, tools dealing with gene signatures have been devel- various treatment targets have been deﬁned and oped to date. One of the signatures, PAM 50, estimates have enabled efﬁcient therapeutic strategies in breast the intrinsic subtype by the gene signature and pro- cancer (BC). In order to offer the most suitable treat- vides additional prognostic information . Oncotype includes 21 genes for the prediction of the recurrence risk and enables the stratiﬁcation into three groups: Dr. med. univ. E. V. Klocker ()· low, intermediate and high risk . Sparrano et al. Assoz. Prof. PD Dr. med. univ. et scient. med. M. Balic randomized 6711 patients with HR+, HER2–, lymph Department of Oncology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria node negative (N–) breast cancer with an intermediate firstname.lastname@example.org recurrence score of 11–25 between chemotherapy plus endocrine treatment and endocrine treatment alone Assoz. Prof. PD Dr. med. univ. et scient. med. M. Balic in a prospective trial. In the total cohort no bene- email@example.com ﬁt from adding adjuvant chemotherapy in interme- Univ.-Prof. Dr. G. Steger diate risk patients was shown. Nonetheless, women Department of Internal Medicine I, Division of ≤ 50 years old with a recurrence score of 16–25 re- Oncology, Medical University of Vienna, Waehringer ceiving chemotherapy in combination with endocrine Guertel 18–20, 1090 Vienna, Austria firstname.lastname@example.org K Molecular proﬁling in breast cancer short review therapy were more likely to show a beneﬁt in disease- under evaluation . Patritumab deruxtecan showed free survival (DFS) . efﬁcacy and tolerability in a phase 1 study including 21 pretreated metastatic breast cancer patients . This ADC showed also promising results in a phase Challenging the deﬁnition of intrinsic subtypes 1 study in nonsmall cell lung cancer, especially in pa- tients with higher HER3 expression . However, tar- HER2 low geting HER3 in breast cancer is still a future goal and The transmembrane tyrosine kinase receptor HER2 needs to be studied further. represents a well-established treatment target. HER2 positivity is deﬁned by the American Society of Clin- TNBC ical Oncology/College of American Pathologist as immunohistochemistry (IHC)+++ . In tissues with TNBC lacking estrogen receptor (ER)–, progesteron IHC++, meaning a weak to moderate membrane receptor (PR)–, and HER2 remains a treatment chal- staining in > 10% of tumor cells, a reﬂex in situ hy- lenge. As shown by Burstein et al. and others, TNBC bridization (ISH) is recommended . If tissue is is a heterogeneous disease. Burstein et al. deﬁned IHC 0 or IHC+, the result is HER2 negative (HER2–) 4 TNBC subtypes using a PAM50 gene signature: lu- . However, HER2 low is IHC+ or IHC++ with a neg- minal androgen receptor (LAR), mesenchymal (MES), ative ISH result. basal-like immunosuppressed (BLIS) and basal-like Due to the development of antibody–drug conju- immune activated (BLIA) . Androgen-receptor gates (ADCs), HER2 low has reached a new signiﬁ- (AR) might represent a treatment target, as AR– in- cance. ADC trastzumab–deruxtecan (T-Dx) shows ef- hibitors were studied in AR expressing TNBC and fectiveness in HER2+, HER2 low and also in HER2 het- showed clinical response . The recently developed erogeneous BC by the bystander killing effect [6–8]. ADC sacituzumab–govitecan, targeting the antithro- The phase III trial was presented at ESMO 2021 and phoblast cell–surface antigen 2 (TROP2) has shown a signiﬁcantly longer DFS and overall survival (OS) promising results in heavily pretreated patients with compared to trastuzumab-emtansine (T-DM1) in sec- TNBC . Further studies in triple negative and ond line was detected in HER2+ mBC patients . also HER2-BC are ongoing. To date, no selection by Phase III trials are ongoing in HER2 low patients. TROP2 expression is needed due to the bystander Another second-generation antibody conjugate killing effect, but the efﬁcacy is clearly correlated with targeting HER2 is SYD958, called trastuzumab duo- the level of TROP2 expression. carmazine, with an ongoing phase III study TULIP, which showed promising results in the ﬁrst analysis Potential of liquid biopsy presented at ESMO 2021. It showed efﬁcacy in heavily pretreated, HER2+, HER2 low, and T-DM1 Over the last decade, an increasing number of tech- resistant breast cancers in a phase I trial . nologies to comprehensively analyze circulating de- oxyribonucleic acid (DNA) and particularly the tu- mor fraction have evolved and now various possibil- HER2 mutations ities for mutation testing are provided [21–23]. The Beyond HER2 low BC, ERB2 mutations remain a treat- phase 2a plasmaMATCH trial selected patients for ment challenge. HER2 mutationsfunction asdriver speciﬁc treatment based on detection of mutations mutations in tumors without an ampliﬁcation of in circulating tumor DNA. The sensitivity and speci- HER2 too . Tyrosine kinase inhibitors, such as ﬁcity in the circulating tumor DNA were comparable HER2 targeting neratinib are able to directly inhibit with mutation testing in tumor tissue for protein intracellular signaling and have demonstrated their kinase B 1 (AKT1), HER2, and phosphoinositide-3-ki- efﬁcacy in HER2 mutations . nase, catalytic, alpha polypeptide (PIK3CA) mutations . This trial paved the way for future personalized oncology approaches. HER3 Another example in endocrine therapy-resistant As HER2 needs another member of the ERB family to breast cancers is the acquired estrogen receptor 1 build heterodimers for signaling, human epidermal (ESR1) mutation [24, 25]. The detection of ESR1 growth factor receptor 3 (HER3) plays a role in HER2+ mutation in plasma after progression on aromatase breast cancers. HER3 appears to be a part of an es- inhibitor could be used for endocrine treatment de- cape mechanism in HER2 targeting treatments. As cision . Fulvestrant has shown efﬁcacy in ESR1- a result, HER3 and its mechanisms in signaling have mutated breast cancer  and clinical trials are now been widely studied. There is evidence that HER3 testing the hypothesis in larger patient cohorts. is essential for the HER2 driven phosphatidylinosi- tol 3-kinase-protein kinase B (PI3K-AKT) pathway by binding heterodimers with HER2 . The ADC patri- tumab deruxtecan which speciﬁcally binds to HER3 is Molecular proﬁling in breast cancer K short review Table 1 Therapeutic agents and their targets Target Setting Therapeutic agent Germline mBCRA1/2 Adjuvant, palliative PARP inhibitors HER2 Neoadjuvant, adjuvant, Trastuzumab, pertuzumab, palliative neratinib, lapatinib, tucatinib, T-DM1, T-Dx HER2 mutations Palliative Neratinib, lapatinib, tucatinib HER2 low/HER2 heterogeneity In development palliative T-Dx HR Neoadjuvant, adjuvant, SERM, AI palliative PIK3CA Palliative Alpelisib PD-L1/CPS Palliative, neoadjuvant? Atezolizumab, pembrolizumab PTEN, AKT Palliative? AKT inhibitors? TROP2? Palliative Sacituzumab–govitecan HER2 Human epidermal growth factor receptor 2, HR hormone receptor, PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide, PD-L1 Programmed death-ligand 1, CPS combined positive score, PTEN phosphatase and tensin homolog, AKT protein kinase B, TROP2 antithrophoblast cell–surface antigen 2, T-DM1 trastuzumab–emtansine, T-Dx trastuzumab–deruxtecan, SERM selective estrogen receptor modulators, AI aromatase inhibitors Biomarkers with therapeutic relevance BRCA 1/2 mutation Besides the well-known HR and HER2 status, which In HER2– disease, PARP inhibitors represent an ac- became relevant during the 1990s, more biomarkers tive agent in germline-mutated BRreat CAncer gene have gained therapeutic importance (Table 1). (BRCA1/2) mBC [32, 33]. In mBC PARP inhibitors sig- niﬁcantly prolong PFS [32, 33]. No signiﬁcant im- pact in overall survival (OS) has been be detected. PIK3CA mutation In ovarian cancer these agents are effective in both The establishment of alpelisib in the therapy algo- germline and somatic mutations . However, the rithm of PIK3CA-mutated metastatic HR+, HER2– BC role of somatic BRCA1/2 mutations or “BRCAness” in requires testing for this mutation . Although the BC is not fully clariﬁed to this date. In the GeparOLA PIK3CA mutation is an early mutation, an acquired trial, for example, germline and somatic BRCA1/2 and PIK3CA mutation may occur under CDK4/6 inhibitor additional mutations leading to homologous recom- treatment associated with resistance to these drugs binant deﬁciency were included . The effect of . While the SOLAR trial demonstrated efﬁcacy of olaparib as an additional neoadjuvant agent was su- alpelisib particularly in PIK3CA-mutated patients , perior only in germline-mutated BRCA1/2 patients in in the BYlieve trial alpelisib showed a signiﬁcant im- the HR+ and in the < 40 years subgroups . An- pact on progression free survival (PFS) after progress other trial including germline mutations, somatic mu- on CDK4/6 . In this trial, PIK3CA mutation test- tations, BRCA1/2 methylation status and BRCA 1/2 ing was done by NGS or PCR in circulating DNA in messenger RNA (mRNA) analyzing the effect of carbo- addition to tumor tissue . platin versus docetaxel in metastatic setting showed an effect of carboplatin solely in the germline-mu- tated cohort . Nonetheless, only a small num- PI3K/AKT pathway ber of patients revealed a germline mutation in this Changes in the PI3K/AKT pathway like phosphatase study. The signiﬁcance of somatic BRCA1/2 muta- and tensin homolog (PTEN) loss or hyperactivated tions ora “BRCAnesstype” fortreatment in BC has not AKT represent potentially useful treatment targets yet been conﬁrmed. Further studies are needed, and . The PI3K/AKT signaling pathway plays an im- one of the trials is the ABCSG45 neoadjuvant phase II portant role in breast cancer. PTEN possesses an study evaluating the combination of carboplatin and inhibiting role, whereas AKT holds an activating func- olaparib versus standard neoadjuvant chemotherapy tion. The AKT inhibitors capivasertib and ipatasertib in patients with “BRCAness”. Germline BCRA1/2 mu- showed promising results in the phase II trials LOTUS tation testing is becoming an imperative for TNBC and and FAKTION [29, 30]. However, the phase III trial high-risk hormone receptor positive BC patients in IPATunity130 with ipatasertib in combination with the adjuvant setting based on the adjuvant OlympiaD paclitaxel in metastatic TNBC (mTNBC) failed to con- trial. Administration of olaparib for 1 year after ﬁn- ﬁrm its beneﬁt . A biomarker analysis of the ishing adjuvant/neoadjuvant treatment in high risk IPATunity130 is planned and may provide additional germline-mutated BRCA1/2 patients leads to an im- information about the subgroups. 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Ipatasertib plus pacli- taxel versus placebo plus paclitaxel as ﬁrst-line therapy for 7 For latest news from interna- metastatic triple-negative breast cancer (LOTUS): a mul- ticentre, randomised, double-blind, placebo-controlled, tional oncology congresses see: phase2 trial. LancetOncol. 2017;18(10):1360–72. http://www.springermedizin.at/ 31. Dent R, Kim SB, Oliveira M, et al. Double-blind memo-inoncology placebo-controlled randomized phase III trial evalu- ating ﬁrst-line ipatasertib combined with paclitaxel for -PIK3CA/AKT1/PTEN-altered locally advanced un- resectable or metastatic triple-negative breast cancer: K Molecular proﬁling in breast cancer
memo - Magazine of European Medical Oncology – Springer Journals
Published: Feb 15, 2022
Keywords: oncology; medicine/public health, general
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