Integrating genomic profiling and targeted therapies in breast carcinoma

In many nations, there is significant concern regarding the rising incidence of breast malignancies among the female population 1. According to the World Health Organization (WHO), in 2022, breast cancer accounted for approximately 2.3 million cases globally, representing 11.6 percent of all reported cancer incidences (). Consequently, it is now recognized as the most pervasive type of cancer across both genders in 156 out of the 185 countries analyzed 2. In addition, it remains one of the most lethal malignancies and was estimated to have caused around 670,000 deaths in 2022; thus, it is the leading cause of cancer-related mortality, particularly for women worldwide 3. While various diagnostic modalities and therapeutic interventions have been developed, the inherent biological complexity of the disease remains a formidable challenge.

Heterogeneity of breast tumors

Breast cancer is not a single pathological entity but rather a highly heterogeneous disease; this realization represents one of the most critical advancements in the field of oncology 4. It comprises a spectrum of biologically heterogeneous subtypes defined by distinct molecular and genetic profiles. Such insights have fostered the development of precision oncology, which focuses on the unique molecular signatures of a patient’s malignancy. At the heart of this approach is genomic characterization, which has transformed the understanding and management of breast cancer by facilitating the identification and implementation of personalized therapeutic regimens 4,5.

For extended periods, breast cancer management relied upon generalized therapeutic strategies, including chemotherapy, radiation, and hormonal therapies 6,7. Although these modalities have saved many lives, they do not account for the genetic and molecular heterogeneity inherent in the tumor. Therefore, their efficacy is patient-specific, and patients may experience significant adverse effects with marginal clinical improvement 8. In response to this therapeutic gap, genomic profiling has been developed to elucidate the precise genetic profile of each tumor. This technique analyzes gene amplification, somatic mutations, and other alterations in the molecular landscape, including the DNA and RNA of tumor cells 9.

Literature search methodology and risk-of-bias assessment

To enhance transparency and reproducibility, this review was conducted using a systematic literature-search strategy adhering to the PRISMA guidelines for scoping reviews. Three major electronic databases—PubMed/MEDLINE, Scopus, and Web of Science—were comprehensively searched up to June 30, 2024. The search strategy was developed to capture both preclinical and clinical studies relevant to breast cancer therapeutics, involving HER2-targeted monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs), antibody-drug conjugates (ADCs), mutations, PARP inhibitors, and RNA-modifying enzymes including ALKBH5, METTL3, and FTO. Keywords and Medical Subject Headings (MeSH) terms were combined using Boolean operators: ("HER2" OR "ERBB2") AND ("breast cancer") AND ("antibody drug conjugate" OR "trastuzumab" OR "pertuzumab" OR "tyrosine kinase inhibitor") AND ("resistance" OR "clinical trial"); and ("BRCA1" OR "BRCA2") AND ("breast cancer") AND ("PARP inhibitors" OR "olaparib" OR "talazoparib" OR "niraparib"). For RNA-modifying enzymes, the search included terms such as ("ALKBH5" OR "METTL3" OR "FTO") AND ("m6A modification") AND ("breast cancer"). Reference lists of pivotal articles and reviews were manually searched to ensure comprehensive coverage.

Inclusion criteria were: (i) original peer-reviewed articles, systematic reviews, or meta-analyses; (ii) clinical trials (phases I–III) and major observational studies reporting therapeutic efficacy, resistance mechanisms, or genomic profiling insights in breast cancer; and (iii) mechanistic preclinical studies utilizing cell lines or animal models that addressed HER2-targeted therapy, PARP inhibitors, or RNA-modifying enzymes. Only studies published between January 2015 and June 2024 and written in English were included. Exclusion criteria comprised: (i) case reports, conference abstracts, and unpublished theses; (ii) studies with insufficient or anecdotal data; and (iii) reports lacking direct relevance to breast cancer or genomic-targeted therapy.

The final dataset consisted of approximately 90 publications, including 22 clinical trials (comprising randomized controlled trials and Phase II/III studies), 10 systematic reviews/meta-analyses, and over 50 mechanistic/preclinical studies. Clinical trial identifiers (NCT numbers) were extracted and are presented in the relevant tables to ensure traceability.

Methodological quality and risk-of-bias assessments were conducted. For clinical trials, methodological rigor was evaluated by examining trial phase, randomization protocols, blinding procedures, sample size, and the completeness of outcome reporting. Trials with limited cohort numbers, a lack of blinding, or incomplete reporting were identified as carrying a higher risk of bias. For preclinical studies, we considered experimental reproducibility, the use of appropriate controls, and independent validation. While the heterogeneity of the included studies precluded a universal scoring system, the Cochrane Risk-of-Bias 2 (RoB 2.0) tool was applied where appropriate to evaluate five domains: (i) the randomization process, (ii) deviations from planned interventions, (iii) missing outcome data, (iv) measurement of the outcomes, and (v) selection of the reported results. These domains were rated as "low risk," "some concerns," or "high risk."

An overview of ten prominent randomized trials involving HER2-targeted and PARP-inhibitor therapies is provided in Table X, facilitating a rapid assessment of the available level of evidence. The majority of Phase III studies (e.g., CLEOPATRA, DESTINY-Breast03, OlympiAD) utilizing large-scale, multicenter designs demonstrated robust randomization and objective endpoints with minimal attrition bias. However, some open-label designs (e.g., SOPHIA, BROCADE3) presented a moderate risk of performance bias.

Monoclonal antibodies and tyrosine kinase inhibitors overview

A multicenter, randomized, double-blind, placebo-controlled, Phase III trial was conducted at 495 research centers across North America, Europe, Asia, and South America to evaluate the efficacy of neratinib—an irreversible tyrosine kinase inhibitor (TKI) targeting HER1, HER2, and HER4—in patients with malignant breast carcinoma. The study enrolled 2,840 women aged 18 years or older with stage I–III HER2-positive breast cancer who had previously completed chemotherapy and trastuzumab-based adjuvant therapy. Participants were randomly assigned to receive either neratinib (240 mg/day) or a placebo for one year.

Two-year follow-up data demonstrated that neratinib significantly improved invasive disease-free survival compared to the placebo group. The cancer-free survival rate was 93.9% in the neratinib group versus 91.6% in the placebo group, representing a 33% reduction in the risk of disease progression or death ($p = 0.0091$) 28. However, neratinib was associated with a higher incidence of adverse events, specifically diarrhea; therefore, proactive management and continued longitudinal follow-up are required for further clinical assessment. The biochemical mechanism of TKIs in HER2-positive breast cancers is illustrated in Figure 229.

In a subsequent phase 1b clinical study, tucatinib (an oral, highly potent HER2-selective tyrosine kinase inhibitor) was evaluated as a novel treatment in combination with ado-trastuzumab emtansine (T-DM1) in patients with advanced HER2+ breast cancer, regardless of the presence of brain metastases. The study established the recommended dosages of tucatinib when administered in combination with T-DM1. Borges et al. 30 enrolled 57 participants aged ≥18 years with HER2+ metastatic breast cancer. Prior to enrollment, patients had received previous treatment with trastuzumab, pertuzumab, and T-DM1. The results suggest that the recommended dose of tucatinib is 300 mg twice daily.

In the clinical study known as the CLEOPATRA trial, Swain et al. evaluated HER2+ metastatic breast cancer patients who had not previously received chemotherapy or targeted therapy for metastatic disease. Participants were randomized to receive pertuzumab in addition to trastuzumab and docetaxel. The results demonstrated a significant extension of overall survival (OS; p < 0.001) and progression-free survival (PFS) by approximately 56.5 months and 18.5 months, respectively 31.

Yi et al. 34 conducted a study to investigate HER2 mutations in metastatic breast cancer (MBC) and evaluate the efficacy of pyrotinib in patients harboring these mutations. The study enrolled 1,184 patients with invasive breast cancer to characterize mutation profiles using circulating tumor DNA (ctDNA) sequencing via a 1021-gene panel. ctDNA sequencing identified 105 patients (8.9%) with HER2 mutations, comprising both amplification-positive and amplification-negative cases. A significantly higher frequency of mutations was observed in patients with HER2 amplification compared to those with negative amplification (19.5% vs. 4.8%, p < 0.001). Furthermore, progression-free survival (PFS)—calculated from treatment initiation (trastuzumab or pyrotinib therapy) to the date of disease progression—was notably shorter in HER2-mutated patients relative to those with wild-type HER2. In the subsequent phase II study, pyrotinib demonstrated a 40% objective response rate in patients with non-amplified MBC harboring kinase domain mutations. Conversely, patients with concurrent HER2 amplification and extracellular domain mutations demonstrated resistance to pyrotinib therapy.

Collectively, HER2-targeted tyrosine kinase inhibitors (TKIs) demonstrate how variations in molecular selectivity, treatment settings, and clinical profiles affect tolerability and efficacy. Neratinib, an irreversible inhibitor, demonstrated a moderate and statistically significant improvement in two-year invasive disease-free survival when administered as adjuvant therapy following trastuzumab; however, it was associated with significant diarrhea due to off-target inhibition of EGFR and HER4. This broad receptor inhibition limits treatment adherence and necessitates proactive symptom management 35. In contrast, tucatinib—a highly selective HER2 inhibitor—exhibited superior tolerance and central nervous system (CNS) activity when combined with ado-trastuzumab emtansine, thereby providing clinical benefits to patients with brain metastases 36. Furthermore, pertuzumab, a monoclonal antibody that prevents HER2 dimerization at the extracellular domain, achieved the most significant improvement in overall survival and PFS when combined with trastuzumab and docetaxel in the CLEOPATRA trials 37. Simultaneously, pyrotinib showed promising efficacy in HER2-mutated cancers (specifically kinase domain mutations), though resistance remains a critical concern 34.

The major challenge in treating HER2-positive breast carcinoma is the development of resistance to standard-of-care agents such as trastuzumab and lapatinib. To address this, Liu et al. 38 investigated the role of the $m^6A$ demethylase enzyme ALKBH5. ALKBH5 expression is significantly upregulated in breast carcinoma, where it promotes cancer cell progression by stabilizing GLUT4 mRNA. By removing $m^6A$ modifications, ALKBH5 increases the stability of GLUT4 transcripts, leading to upregulated GLUT4 protein expression and enhanced glycolysis. Consequently, Liu demonstrated that targeting the ALKBH5/GLUT4 pathway through genetic knockdown or knockout may serve as a viable therapeutic strategy for HER2-positive breast cancer 39.

Antibody Drug Conjugates (ADC) against HER-2 +ve cancers

In addition to these treatments, antibody-drug conjugates (ADCs)—which comprise a monoclonal antibody linked to a cytotoxic drug via a molecular linker—have demonstrated remarkable efficacy in the treatment of HER2-positive (HER2+) malignant breast carcinoma. These conjugates combine monoclonal antibodies for direct receptor blockade with small molecule cytotoxic drugs to induce apoptosis and inhibit tumor growth 34,35. The mechanisms of action triggered by ADCs include antibody-dependent cellular cytotoxicity (ADCC) 36 and complement-dependent cytotoxicity (CDC), as shown in Figure 3. HER2-targeted ADCs deliver lethal payloads to malignant cells via monoclonal antibodies such as trastuzumab, which binds to HER2, thereby disrupting signaling pathways and hindering tumor progression 37. ADCs utilizing cleavable linkers release their cargo into the tumor microenvironment or within target cells, triggering the bystander effect to eliminate adjacent HER2-negative cells; conversely, non-cleavable or rigid linkers release cargo exclusively within the target cells. Further, ADCs inhibit HER2 shedding and enhance cytotoxicity via ADCC and CDC, thereby increasing therapeutic efficacy 38.

While ADCs are promising therapeutic agents, resistance to trastuzumab-based conjugates remains a major barrier in breast cancer treatment, prompting the development of novel ADCs to mitigate these challenges. In the case of trastuzumab emtansine (T-DM1), resistance occurs via the downregulation of the target antigen (HER2), heterogeneous HER2 expression, or HER2 truncation and heterodimerization, which prevents ADC binding 39. Additionally, even upon successful binding, the receptor-antibody complex may fail to internalize efficiently or may be misrouted within the cell, failing to reach the lysosomes for drug release; such impaired internalization, trafficking, and lysosomal dysfunction result in the loss of cytotoxic efficacy 40. Furthermore, increased expression of ATP-binding cassette (ABC) transporters is linked to T-DM1 resistance, as these transporters efflux excessive drug from the cell 41. Consequently, modifying ADC internalization and trafficking, or inhibiting ABC transporter expression, represent viable strategies to overcome resistance.

DESTINY-Breast01 (NCT03248492), a multicenter, single-arm study funded by Daiichi Sankyo and AstraZeneca, evaluated the safety and efficacy of trastuzumab deruxtecan (DS-8201a) against advanced HER2+ breast cancer 42. The study cohort comprised patients heavily pretreated with a median of six prior therapies, including T-DM1, indicating resistance to existing regimens. The outcomes were significant, with an objective response rate (ORR) of 60.9%. Among these, 6% achieved a complete response, while 54.9% exhibited significant tumor shrinkage, indicating that DS-8201a superior efficacy compared to available therapies. In 2019, it was approved for adults with unresectable or metastatic HER2+ breast carcinoma 42. In DESTINY-Breast03 (NCT03529110), trastuzumab deruxtecan (T-DXd) was compared with T-DM1 in patients previously treated with trastuzumab and a taxane. This Phase III, open-label, randomized trial showed significant improvement in progression-free survival (PFS) with T-DXd; at 12 months, 76% of patients in the T-DXd arm were alive without disease progression, compared to 34.1% in the T-DM1 arm. The overall survival (OS) rate was 94.1% for T-DXd and 85.9% for T-DM1. However, adverse events were more prevalent with T-DXd, including interstitial lung disease (ILD) in 10.5% of patients versus 1.9% for T-DM1. Overall, T-DXd exhibited superior efficacy over T-DM1, representing an effective treatment option for HER2+ breast cancer 43.

The Phase III DESTINY-Breast04 trial was conducted on patients with low HER2 expression levels, for whom most HER2-targeted therapies are typically ineffective. The study examined the efficacy of T-DXd in HER2-low cancers following prior chemotherapy. Results demonstrated improved PFS (10.1 vs. 5.4 months; Hazard Ratio [HR] 0.51; P < 0.001) in the hormone receptor-positive cohort. Similarly, OS was improved (23.9 vs. 17.5 months; HR 0.64; P = 0.003). However, 52.6% of patients experienced serious adverse events, 12% developed ILD, and 0.8% of cases were fatal. Overall, median PFS and OS were improved using T-DXd compared to traditional chemotherapy 43,44. Several other trials, including DESTINY-Breast 05, 06, 08, 09, and 11, are currently ongoing (NCT04622319, NCT0449425, NCT04556773, NCT04784715, NCT05113251).

Similarly, other ADCs such as ARX788 and ZW49 are undergoing Phase I clinical trials. ARX788 is an anti-HER2 ADC conjugated to monomethyl auristatin F (MMAF), a microtubule inhibitor 45, while ZW49 is a bispecific antibody (ZW25) conjugated to monomethyl auristatin E (MMAE), which internalizes rapidly into HER2-expressing cells 46. MEDI4276, another bispecific antibody conjugated to a tubulysin-based microtubule inhibitor, targets HER2-overexpressing cells, including those resistant to T-DM1; however, its Phase I trial was limited by toxicity 47.

SYD985 (trastuzumab duocarmazine) is an ADC combining trastuzumab with a duocarmycin alkylating agent via a cleavable linker. The cleavable linker releases the payload extracellularly, demonstrating strong activity against HER2-low tumors. Phase I trials indicated an ORR of 33% and a median PFS of 9.4 months 48; the Phase III TULIP trial is ongoing. In a late-stage clinical trial comparing T-Duo (SYD985) with physician’s choice (PC) in patients with unresectable advanced carcinomas, 437 patients (291 in the T-Duo arm and 146 in the PC arm) with a median age of 56 were enrolled. The median PFS was 7 months for T-Duo compared to 4.9 months for PC, with a median OS of 20.4 months versus 16.3 months, respectively. The ORR was 27.8% for T-Duo and 29.5% for PC. Although T-Duo improved PFS relative to PC, it exhibited higher ocular toxicity (52.8%) compared to PC (48.2%) 49, highlighting a need for more innovative strategies.

In summary, ADCs for HER2+ breast cancer show variations in efficacy, safety, and resistance governed by molecular design, patient profiles, and clinical settings. Second-generation ADCs like T-DXd have shown superior response rates and PFS compared to T-DM1, as evidenced in the DESTINY-Breast03 trial 43. This superiority is attributed to the higher drug-to-antibody ratio, membrane-permeable payload, and bystander killing effect, notwithstanding the higher risk of ILD. In contrast, T-DM1 maintains activity with mild systemic toxicity. Other agents designed with cleavable linkers (e.g., SYD985) or engineered bispecifics (e.g., ZW49 and MEDI4276) address tumor heterogeneity but are limited by organ-specific toxicities. ABC transporter overexpression, impaired trafficking, and HER2 downregulation contribute to resistance. Overcoming these barriers requires improving internalization and optimizing linkers. Currently, T-DXd is the most effective ADC for both HER2-positive and HER2-low tumors. Future priorities should focus on improving linker-payload stability and mitigating pulmonary toxicity 45,46,47,48.

Effectiveness of PARP inhibitors in clinical trials

By inhibiting PARP enzyme activity and the subsequent PARylation process, PARP inhibitors (PARPi) are designed to impede DNA repair. Their mechanism of action involves competing with NAD+ for binding to the PARP catalytic domain. In 2005, two independent groups demonstrated that PARP inhibition induces synthetic lethality in BRCA1- and BRCA2-mutant cancers, highlighting a strong synergistic relationship between BRCA function and PARP1 activity 39.

In the presence of PARPi, endogenously produced single-strand breaks (SSBs) are converted into double-strand breaks (DSBs) during cell division due to the impairment of base excision repair (BER). While normal tissues possessing at least one wild-type gene copy can repair DSBs via functional homologous recombination (HR), cells with BRCA dysfunction are unable to repair this damage and undergo apoptosis. In patients with germline BRCA mutations, tumor cells typically exhibit biallelic deficiency and faulty HR, whereas normal tissues maintain BRCA proficiency 40.

Other pathways underlying the anticancer activity of PARPi have recently been identified. A primary mechanism is the "trapping" of PARP1 onto damaged DNA; the resulting PARP-DNA complexes obstruct both transcription and DNA replication. This process is driven by allosteric conformational changes in PARP1 and PARP2 that stabilize their association with DNA, acting independently of catalytic inhibition. Notably, the cytotoxic potency of a PARP inhibitor correlates with its ability to induce PARP1 trapping and the accumulation of these toxic PARP-DNA complexes 41.

Furthermore, BRCA1 mutations that impair heterodimerization with BARD1 lead to aberrant PAR formation and disrupted recruitment of BRCA1/BARD1 complexes to DNA damage sites, ultimately impairing HR-mediated repair and triggering cell death. The PARPi mechanism also involves the activation of non-homologous end joining (NHEJ), because inhibited PARP1 is less effective at preventing KU proteins from interacting with free DNA ends 42. Excessive NHEJ activation leads to genomic instability and eventual cancer cell death. Additionally, inhibition of PARP1 prevents alternative end-joining (Alt-EJ) activation, further promoting apoptosis.

Finally, the effects of PARPi are mediated by the upregulation of death receptors DR5 and FAS via the activation of the SP1 and NF-κB transcription factors. This sensitizes tumor cells to TRAIL or FASL death receptor ligands, as shown in Figure 5. In summary, PARPi induce cell death by trapping PARP1/2 on damaged DNA, inhibiting Alt-EJ-mediated repair in HR-deficient cells, and promoting death receptor upregulation through SP1 and NF-κB signaling 43.

Clinical Developments in breast cancer

In BRCA-mutated cancers, various PARP inhibitors (PARPi) have been studied. Two primary strategies have been employed to expand PARPi clinical applications: PARPi monotherapy in cancers with defective DNA damage repair pathways, and the use of PARPi in combination with DNA-damaging chemotherapy 39. Currently, five PARPi are under investigation in clinical trials: veliparib, olaparib, rucaparib, niraparib, and talazoparib. The agent iniparib was originally developed as a PARPi 40; however, following unfavorable outcomes in a Phase III trial evaluating the drug combined with platinum and gemcitabine for metastatic triple-negative breast cancer (TNBC), subsequent investigations demonstrated that iniparib fails to inhibit PARP . As tumor sensitivity to platinum agents correlates with the presence of homologous recombination (HR) deficiency, platinum-sensitive tumors are expected to respond to PARPi therapy 41.

The potency of PARP inhibitors (PARPi) regarding PARP trapping and catalytic inhibition varies significantly, as delineated in Table 3. Notably, the magnitude of PARP enzyme inhibition does not directly correlate with the extent of PARP trapping. Among the clinically available PARPi, talazoparib exhibits the most potent catalytic inhibition, demonstrating approximately 100 times greater efficacy than niraparib. While rucaparib, olaparib, and niraparib similarly induce PARP trapping, talazoparib remains the most potent trapper. Conversely, although veliparib has been reported to induce PARP trapping, this mechanism appears to be least pronounced with this agent 42.

Given that talazoparib exerts the most profound effect, these variations in inhibitory effectiveness and trapping capacity may serve as biomarkers for PARPi cytotoxicity in BRCA-mutant cancers; however, further research is required to determine if these properties translate into superior clinical outcomes. Furthermore, the maximum tolerated dose of monotherapy or combination regimens with chemotherapy may be limited by the increased cytotoxicity associated with PARP trapping, which can exacerbate adverse events, such as cytopenias 49,50.

Clinical trial of PARPi for the treatment of BRCA1/2 mutated cancers

Following the successful development of PARP inhibitors (PARPi) for BRCA-mutated metastatic breast cancer, clinical trials are currently examining their impact in early-stage disease within both neoadjuvant and adjuvant settings. The I-SPY 2 trial is a multicenter, randomized, phase 2 platform utilizing numerous experimental arms to evaluate the addition of new medications or combinations to standard neoadjuvant chemotherapy. The primary endpoint of this trial is pathological complete response (pCR). In one arm, patients with triple-negative breast cancer (TNBC) were randomized to receive either paclitaxel alone or veliparib (50 mg BID for 21 days) in conjunction with carboplatin for four cycles 51.

Following therapy, all patients received four cycles of doxorubicin and cyclophosphamide (AC), followed by surgery. The standard therapy arm (paclitaxel followed by AC) achieved a pCR rate of 26%, whereas the investigational veliparib/carboplatin arm demonstrated an estimated pCR rate of 52%. Pathologic complete response serves as a surrogate endpoint for improved event-free survival in breast cancer. Notably, information regarding germline BRCA mutation status for this cohort has not yet been released.

Subsequently, the BrighTNess Phase 3 trial was designed to evaluate the addition of carboplatin and veliparib to standard neoadjuvant chemotherapy. Researchers randomly assigned stage II-III TNBC patients to receive either carboplatin plus veliparib, carboplatin alone, or placebo 52. Additionally, neoadjuvant talazoparib monotherapy demonstrated significant activity in a pilot phase 2 study. After two months of treatment, 13 patients with BRCA-mutant breast cancer showed a median ultrasound-measured tumor shrinkage of 88% (range 30–98%). This research was terminated early in order to expand the investigation of neoadjuvant talazoparib as a standalone preoperative treatment and further evaluate the pCR rate 53.

The effect of PARP inhibitors on BRCA1 and BRCA2 tumor cells

For patients with BRCA-mutant triple-negative breast cancer (TNBC) or hormone receptor-positive, HER2-negative breast cancer, the phase 3 OlympiA trial evaluated the safety and efficacy of adjuvant olaparib (300 mg BID) versus placebo for a maximum duration of 12 months. Eligible patients were required to have completed neoadjuvant or adjuvant chemotherapy in addition to definitive local therapy. Randomization was stratified by prior neoadjuvant versus adjuvant chemotherapy, previous platinum chemotherapy use, and hormone receptor status 54.

In the post-neoadjuvant cohort, patients without a pathological complete response (pCR) were included. The primary endpoint was invasive disease-free survival, while secondary endpoints included safety and tolerability, overall survival, distant disease-free survival, and the incidence of novel primary cancers. Additionally, olaparib is currently being investigated as a neoadjuvant treatment for basal TNBC and BRCA-mutant breast cancer in combination with platinum-based chemotherapy 55.

Furthermore, a phase 2 trial is evaluating rucaparib as maintenance therapy following cisplatin for TNBC and BRCA-mutant breast cancer with residual disease after neoadjuvant anthracycline- and taxane-based therapy. Following 2 to 4 weeks of cisplatin, patients were randomized to receive cisplatin with or without rucaparib. According to preliminary data, patients treated with an anthracycline-containing regimen showed a significant improvement in two-year disease-free survival with the addition of rucaparib to cisplatin (69.9% vs. 55.9%). Notably, the benefit to disease-free survival was unaffected by BRCA mutation status 56.

Increasing the Clinical Use of PARPi

The concept of synthetic lethality as a therapeutic approach has been validated by the anti-tumor efficacy of PARP inhibitors (PARPis) in BRCA-mutated breast and ovarian carcinomas. Furthermore, evidence of PARPi effectiveness is emerging for other BRCA-mutant malignancies, including prostate and pancreatic cancers. However, it remains to be determined whether this efficacy can be extended to other tumor types lacking germline BRCA1/2 mutations that harbor other defects in DNA damage repair pathways 57.

Recent research has increasingly focused on cancers displaying the "BRCAness" phenotype. "BRCAness" refers to malignant tumors that do not harbor germline BRCA1 or BRCA2 mutations but share clinical and molecular characteristics of homologous recombination (HR) repair failure due to distinct genetic alterations. These include promoter hypermethylation of BRCA1, somatic mutations in BRCA1 or BRCA2, or alterations in other genes involved in double-strand break (DSB) repair. Mirroring BRCA-associated tumors, these cancers exhibit sensitivity to platinum-based chemotherapy 58. Currently, a standardized biomarker for "BRCAness" does not exist, though extensive research has aimed to develop classifiers to predict susceptibility to PARP inhibition. Within the context of the I-SPY2 clinical trial, Severson et al. recently developed a 77-gene signature to define "BRCAness" and evaluate its utility in predicting responses to neoadjuvant veliparib combined with carboplatin 34.

Despite the small sample size, they demonstrated a correlation between the "BRCAness" classification and patient response within the veliparib/carboplatin arm. To quantify "BRCAness," studies are also utilizing an HR deficiency (HRD) score that integrates three distinct indicators of genomic instability: large-scale state transitions, telomeric allelic imbalance, and loss of heterozygosity. Patients with a favorable score (≥42) exhibited improved responses to platinum therapy. This hypothesis is currently being investigated further using other PARPis, such as rucaparib and talazoparib 37. Additionally, clinical investigations are exploring PARPi combinations with immunotherapies, including CTLA-4 and PD-1/PD-L1 antibodies. The enhanced genomic instability in HRD tumors may be linked to an increased neoantigen load, which is associated with a more robust immune response. Supporting this combination strategy, preliminary evidence indicates that PARPis may sensitize tumors to immunotherapy 36.

Moreover, preliminary data suggest that DNA-repair-defective tumors selectively activate the cell cycle-specific STING (stimulator of interferon genes)-dependent innate immune response. Early-phase I studies are assessing the efficacy of the anti-angiogenic agent cediranib or the PD-L1 inhibitor durvalumab in combination with olaparib in women with progressive solid tumors. In a cohort of twelve evaluable patients receiving durvalumab plus olaparib, eight experienced stable disease for more than four months and two achieved a partial response, resulting in an 83% disease control rate. Consequently, trials investigating the combination of PARPis and PD-L1 inhibitors are currently underway 59.

PI3K inhibition represents another strategy to expand the utility of PARP inhibition beyond BRCA-mutant breast tumors. The PI3K/MAPK pathway facilitates DNA break repair within tumor cells in addition to its pro-proliferative and anti-apoptotic roles. In preclinical breast cancer models, the combination of olaparib and a PI3K inhibitor slowed tumor growth, indicating synergy in BRCA-mutant cancers. Preliminary clinical data demonstrated success with the combination of olaparib and the PI3K inhibitor buparlisib (BKM120) in patients with triple-negative breast cancer (TNBC) or ovarian cancer, yielding an overall response rate (ORR) of 24% (10 of 42 patients) 60.

PARPi Resistance

Malignancies may develop resistance to poly (ADP-ribose) polymerase inhibitor (PARPi) therapy, analogous to the development of resistance to other targeted treatments. The restoration of the homologous recombination (HR) repair pathway is one recognized strategy underlying this phenomenon. Reversion mutations that restore BRCA1/2 function and confer PARP resistance have been shown to arise from the enhanced genomic instability associated with PARP inhibition 37,61.

Furthermore, the loss of certain DNA repair proteins, such as REV7 and p53-binding protein 1 (53BP1), can partially restore HR activity in BRCA-deficient cells. Another mechanism of resistance is increased drug efflux mediated by the upregulation of P-glycoprotein expression, which lowers intracellular PARPi concentrations. Additionally, resistance to PARPi can result from variations in PARP1 expression levels within cancer cells.

Elevated PARP1 expression is linked to reduced survival in patients with breast cancer and contributes to PARPi resistance. Although the extent of overlap remains unclear, PARPi and platinum chemotherapy share several potential resistance mechanisms. In platinum-resistant scenarios, these mechanisms may restrict the clinical utility of PARPi; consequently, alternative strategies to counteract acquired resistance are required. Notably, most current PARPi studies exclude individuals with platinum-resistant disease 38.

PARPi for breast cancer approved recently

A Phase I clinical trial demonstrated that a synthetic lethality approach could be successfully implemented by showing that the PARP inhibitor (PARPi) olaparib, which inhibits PARP1 and PARP2, exhibited objective antitumor activity in patients with BRCA-mutated breast, prostate, or ovarian cancers, while demonstrating a more favorable side-effect profile than conventional chemotherapies. Subsequent trials verified that PARPis are more effective as monotherapy for BRCA-mutated ovarian cancer than for BRCA wild-type tumors 59.

In 2014, the European Commission approved olaparib (capsule) for patients with recurrent, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancers who achieved a complete or partial response following platinum-based chemotherapy. The FDA also approved olaparib to treat germline BRCA-mutated advanced ovarian cancer (OC) in patients who had received three or more prior lines of chemotherapy. Subsequently, both the FDA and EMA approved a tablet formulation of olaparib, which reduces the daily pill burden, for maintenance treatment of platinum-sensitive recurrent OC, irrespective of BRCA mutation status 34.

According to Robson and Tung 60, the OlympiAD trial led to the approval of olaparib for patients with previously treated, HER2-negative metastatic breast cancer. Researchers analyzed 302 patients with hereditary BRCA mutations and HER2-negative status, including those with triple-negative disease. Each participant received either olaparib or single-agent chemotherapy (capecitabine, eribulin, or vinorelbine). After a median follow-up of 14.5 months, olaparib exhibited a significantly higher progression-free survival (PFS) rate than conventional treatment 42.

Although PFS improved by only several months, the clinical outcomes remain optimistic. However, the OlympiAD study was unable to evaluate the relative efficacy of PARPis compared to platinum-based chemotherapy in patients with germline BRCA mutations, as PARPi efficacy was not directly compared to platinum compounds. Therefore, additional research is needed to compare PARPis with platinum-based agents in germline BRCA-mutated breast cancer. Furthermore, it remains unknown whether PARPi treatment is efficacious in HER2-negative breast cancer harboring somatic BRCA mutations 61.

Among PARP inhibitors, talazoparib possesses the highest cytotoxicity and the strongest PARP-trapping ability. In contrast, olaparib and niraparib exhibit better tolerability and moderate potency. Rucaparib is effective in combination regimens but demonstrates less catalytic inhibition. PFS outcomes in clinical trials (such as OlympiAD, EMBRACA, and BROCADE3) are superior to those of chemotherapy. Due to variations in patient selection and study design, survival benefits vary among PARP inhibitors.

Talazoparib is associated with higher hematologic toxicity, including neutropenia and anemia, whereas niraparib and olaparib are better tolerated for long-term therapy. Resistance is primarily driven by BRCA reversion mutations that restore DNA repair capacity. Resistance is also mediated by alterations in PARP1 expression and the overexpression of P-glycoprotein. Notably, many platinum resistance mechanisms overlap with PARPi resistance. Variability in clinical outcomes is explained by patient cohorts, BRCA mutation types, and previous platinum exposure.

The antitumor response is improved when PARPis are combined with PI3K or immune checkpoint inhibitors. In addition to delaying the onset of resistance, combined regimens enhance synthetic lethality. While BRCA-mutant tumours still require PARPi monotherapy, the goal of ongoing research is to extend these advantages to "BRCAness" and other homologous recombination (HR)-deficient subtypes.