Introduction: Breast cancer exhibits vast genomic diversity, leading to varied clinical manifestations. Integrating molecular subtyping with in-depth genomic profiling is pivotal for informed treatment choices and prognostic insights. Whole-genome clinical analysis provides a holistic view of genome-wide variations, capturing structural changes and affirming tumor suppressor gene loss of heterozygosity. Case Presentation: Here we detail four unique breast cancer cases from Seoul St. Mary’s Hospital, highlighting the actionable benefits and clinical value of whole-genome sequencing (WGS). As an all-in-one test, WGS demonstrates significant clinical utility in these cases, including: (1) detecting homologous recombination deficiency with underlying somatic causal variants (case 1), (2) distinguishing double primary cancer from metastasis (case 2), (3) uncovering microsatellite instability (case 3), and (4) identifying rare germline pathogenic variants in TP53 gene (case 4). Our observations underscore the enhanced clinical relevance of WGS-based testing beyond pinpointing a few driver mutations in conventional targeted panel sequencing platforms. Conclusion: With genomic advancements and decreasing sequencing costs, WGS stands out as a transformative tool in oncology, paving the way for personalized treatment plans rooted in individual genetic blueprints.

Breast cancer is a major global health concern, characterized by genetic heterogeneity, yielding varying clinical profiles. Four molecular subtypes – luminal A, luminal B, HER2-enriched, and basal-like – are discerned through gene expression profiling, each presenting unique incidence rates, therapeutic responses, disease courses, survival rates, and radiographic features [1].

The classification of these subtypes often depends on surrogate markers like immunohistochemical (IHC) assays (for ER, PR, HER2, and Ki-67), which sometimes fail to define the intrinsic molecular subtype accurately. For instance, around 20% of luminal B tumors are also HER2-positive based on IHC analysis, muddying the diagnostic waters [1].

While targeted panel sequencing platforms offer enhanced value compared to traditional prognostic factors, they do not provide a comprehensive genomic profile as they target only ∼0.1% of cancer genomes. As targeted therapies gain traction and actionable biomarkers gain prominence in clinical guidelines, comprehensive genomic testing becomes paramount. Current targeted panel sequencing tests, due to their update cycles, might lag in recognizing emerging biomarkers [2] and have limits for detecting large and complex structural variation detection as well as for evaluating mutational signatures. Contrarily, WGS provides an all-inclusive genomic snapshot, capturing variations throughout the genome. WGS’s strengths lie in the unbiased detection of structural variations, validating loss of heterozygosity (LOH) in tumor suppressor genes, and recognizing mutational patterns and signatures often associated with homologous recombination deficiency (HRD) and microsatellite instability (MSI) [2]. Its comprehensive nature eliminates the need for frequent panel updates and allows for retrospective analyses as new biomarkers surface.

In this context, we present four breast cancer cases managed using standard-of-care practices in parallel with WGS testing. The goal was to assess the potential of WGS findings to impact treatment strategies and outcomes. The comprehensive genomic profiling in these patients highlights the clinical utility of WGS in a personalized medicine approach to breast cancer. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000536087).

We obtained fully informed consent from the patients for the studies conducted in Seoul St. Mary’s Hospital. Protocols of this study were approved by the institutional review board of the same institution (KC21TISI0007, KC22TISI0292). We adhered to the tenets of the Declaration of Helsinki. All patients underwent routine cancer testing, including IHC and breast MRI, and received standard treatment based on international guidelines (National Comprehensive Cancer Network, etc.). Molecular subtyping of breast cancers was conducted based on the surrogate markers of breast cancer [1].

Fresh frozen tumor tissue and blood samples were taken pre-neoadjuvant chemotherapy (NAC) for DNA extraction, facilitating WGS of the tumor and matched normal tissues. Sequencing and analysis utilized the WGS module of the CancerVision system (Genome Insight, USA), with DNA libraries prepared using TruSeq Nano Kits and sequenced on the Illumina NovaSeq6000 platform (Illumina Inc.) with average depths of coverage of ×40 for tumor samples and ×20 for blood samples. The limit of detection has been established at a 5% variant allele frequency and detection sensitivity for variants under the limit of detection can be compromised. The resultant raw sequences were mapped to the human reference genome build GRCh38 using the BWA-MEM algorithm. PCR duplicate reads were excised using SAMBLASTER. Variant calling for germline small variants utilized HaplotypeCaller and Strelka2, while somatic small variant detection employed Strelka2 and Mutect2. Structural variant identification was conducted via Manta. All variants, both germline and somatic, were annotated using the Variant Effect Predictor and subjected to rigorous manual review and curation within Genome Insight’s proprietary genome browser. The tumor mutation burden (TMB) is quantitatively determined and incorporates a germline subtraction technique to ascertain the number of somatic changes within the entire genome. A TMB value >10 mutations/Mb is classified as “TMB-high.”

In this study, WGS was conducted concurrently as a research initiative, separate from standard medical procedures. This distinction meant that direct clinical intervention based on WGS findings was not feasible. Instead, our focus was on assessing its potential real-world impact within a research context.

Case 1

A 48-year-old woman presented with a rapidly growing tumor in her left breast. Biopsy confirmed it as luminal B type-like invasive breast cancer, with ER and PR positivity (Allred 8/8), HER2 negativity, and Ki-67 index of 88%. A follow-up ultrasound, performed 2 weeks after the initial exam, showed growth from 2.0 cm to 2.8 cm. On breast MRI, the tumor was located in the left breast upper outer quadrant, measuring 2.6 cm (online suppl. Fig. 1), and suspicious lymph nodes were not seen, suggesting clinical T2N0M0. Given its aggressive nature and high Ki-67 index, NAC was recommended, and the patient was treated with doxorubicin/cyclophosphamide followed by paclitaxel.

WGS of the matched normal tissue revealed no pathogenic germline variants associated with breast cancer, including BRCA1 and BRCA2, supporting the tumor’s sporadic genesis. Cancer WGS, with 87% tumor cell fraction and an average ploidy of 2.1, identified 10,664 base substitutions, 3,422 indels, 411 structural variations somatically acquired, and genome-wide copy number alterations (Fig. 1a). The decomposition of mutational signatures from the point mutations indicated that 41.0% and 26.4% of the base substitutions and indels were attributable to SBS3 and ID6, respectively, both linked with flawed HR-based DNA repair [3]. The prevalence of large deletions in SVs (41.6%) further suggested a complete defect in the BRCA2 gene. Indeed, the list of somatic driver mutations (online suppl. Table S1–3) encompassed a BRCA2-disruptive inversion accompanied by a LOH (Fig. 1b). In summary, breast cancer exhibited clear HRD due to complete inactivation of BRCA2 by double somatic hits rather than inherited mutations in the germline.

Fig. 1.

a Circos plot of breast cancer genome of case 1. From the outside of the circle to the inside, the following elements are arranged in their respective orders: cytoband, variant allele fraction of point mutations, intermutational distance of point mutations (logarithmic scale), copy number of each allele (red lines represent major, blue lines represent minor), total copy number (represented by black dots), and structural variations (represented by colored lines). b Somatic BRCA2-disrupting structural variation (inversion) between BRCA2 gene and DGKH gene and loss of heterozygosity in BRCA2 gene (minor copy number: 0).

Fig. 1.

a Circos plot of breast cancer genome of case 1. From the outside of the circle to the inside, the following elements are arranged in their respective orders: cytoband, variant allele fraction of point mutations, intermutational distance of point mutations (logarithmic scale), copy number of each allele (red lines represent major, blue lines represent minor), total copy number (represented by black dots), and structural variations (represented by colored lines). b Somatic BRCA2-disrupting structural variation (inversion) between BRCA2 gene and DGKH gene and loss of heterozygosity in BRCA2 gene (minor copy number: 0).

Close modal

Traditional HRD calculation, an algorithm which combines LOH, telomeric allelic imbalance, and large-scale state transitions, indicated the sample was below the accepted threshold at 42 [4]. The WGS signature-based scoring system, established by combining multiple mutational signatures (such as SBS3, ID6, RS3, and RS5, as well as LOH, telomeric allelic imbalance, and large-scale state transitions) in breast cancers with germline BRCA1/BRCA2 pathogenic variants, deemed the sample HRD-positive (0.99, wherein scores ≥0.7 indicate HRD and scores <0.7 imply HR-proficiency). The tumor showed radiologic complete response (CR) on post-NAC MRI, and pathologic CR (pCR) was subsequently confirmed by wide local excision and sentinel lymph node biopsy.

Case 2

A 34-year-old woman presented with triple-negative breast cancer, exhibiting a high Ki-67 index of 67%. Breast MRI showed a 2.1 cm tumor in the upper inner quadrant of the right breast (online suppl. Fig. 2a) and an enlarged lymph node suspected of metastasis in the right axillary level I, suggesting clinical T2N1. On additional evaluations, abdomen-pelvis CT revealed bilateral ovarian masses and an enlarged aortocaval lymph node. Despite the bilateral nature of ovarian tumors, pelvic MRI (online suppl. Fig. 2b) showed internal T2 high signal intensity with enhancing solid components, indicating primary ovarian cancers rather than metastases. Although contrast-enhanced MRI has an 81% sensitivity and 98% specificity for ovarian cancer diagnosis [5], its discernment between primary and metastatic was not definitive. Bilateral salpingo-oophorectomy and histopathology confirmed high-grade serous cystic carcinoma in both, distinguishing them from breast cancer.

The patient underwent six cycles of docetaxel and carboplatin. Follow-up imaging exams showed size decrease of the aortocaval lymph node and radiologic CR of the breast cancer in abdomen-pelvis CT and breast MRI, respectively. The patient subsequently underwent interval debulking surgery, which included pelvic lymph node and aortocaval lymph node dissections, paired with a nipple-sparing mastectomy and sentinel lymph node biopsy. There was no residual malignancy in either the aortocaval lymph node or the right breast.

WGS aimed to determine: (1) potential germline predisposition variants, despite no familial history of BRCA-associated cancer, and (2) the clonal relationship between the ovarian and breast tumors. To this end, two tumor specimens were secured for WGS: one from a breast core needle biopsy and the other one from salpingo-oophorectomy, with blood as matched normal tissue.

WGS identified a pathogenic germline variant in BRCA1 (c.3593T>A, p.Leu1198Ter) in the matched normal tissue. The breast tumor tissue had a 48% tumor cell fraction, mean ploidy of 3.5, 7,493-point mutations, 268 structural variations, and diverse copy number changes (Fig. 2a), with LOH of BRCA1 and a positive HRD score (0.77). Key driver mutations included MYC amplification (copy number 9), PTEN deletion with LOH, and RAD51B-disruptive variation (intragenic duplication). The ovarian tumor tissue exhibited a 40% fraction, mean ploidy of 4.0, 5,190-point mutations, 268 structural variations, and copy number changes (Fig. 2b). It had an LOH of BRCA1 and an even higher HRD score (0.95). Key driver mutations were a MET amplification, TP53 c.493C>T with LOH, and an NF1-disruptive structural variation (translocation, online suppl. Table S1) with LOH. Both tumor specimens showed LOH of the BRCA1 locus and high HRD scores, suggesting that complete inactivation of BRCA1 gene followed by acquired HRD was the main driver event. Simultaneously, two tumor genomes shared no variants out of thousands of mutations, confirming the dual primary origins.

Fig. 2.

Circos plot of cancer genome and HRD score of case 2. a Right breast. b Left ovary.

Fig. 2.

Circos plot of cancer genome and HRD score of case 2. a Right breast. b Left ovary.

Close modal

Case 3

A 50-year-old woman presented with luminal B type-like breast cancer with low ER positivity (Allred 4), HER2 negativity, and a Ki-67 index of 59%. Breast MRI identified a 4.2 cm tumor in the right subareolar region and an enlarged lymph node in the right axilla (online suppl. Fig. 3a), indicating clinical T2N1. The patient received NAC with adriamycin/cyclophosphamide, followed by docetaxel.

WGS results showed a 55% tumor cell fraction, mean ploidy of 1.6, 22,545 base substitutions, 75,150 indels, and 43 structural variations (Fig. 3). Key driver mutations included AKT1 p.E17K, TP53 p.Q104*, RB1 p.G717Rfs* with LOH, and MLH1 splice site variant with LOH (online suppl. Table S1–3). Mutational signature analysis revealed a predominant presence of defective DNA mismatch repair (MMR)-related signatures in the genome profile of this case, accounting for a total of 42.0% of base substitutions (SBS44, SBS6, SBS26) and 99.8% of indels (ID1, ID2), suggesting the presence of MSI in the tumor. Additionally, APOBEC signatures accounted for 32.8% of base substitutions (SBS2 and SBS13).

Fig. 3.

a Circos plot of breast cancer genome of case 3. b Sequencing and computational assessment of microsatellite instability (MSI) status by MSIsensor2. c Pentaplex PCR assessment of MSI status. d Immunohistochemical assessment of MSI status.

Fig. 3.

a Circos plot of breast cancer genome of case 3. b Sequencing and computational assessment of microsatellite instability (MSI) status by MSIsensor2. c Pentaplex PCR assessment of MSI status. d Immunohistochemical assessment of MSI status.

Close modal

We further evaluated the MSI in the tumor by counting the number of somatic insertions and deletions per million microsatellite loci genome-wide. Typically, a tumor is considered MSI if the rate is over 20%. The tumor’s MSI score was 22.5%, suggesting the presence of MSI. To validate the result, we further conducted MSI-PCR and MMR-IHC in the clinic. While RT-PCR of five conventionally tested MSI markers (BAT-26, NR-24, NR-21, NR-27, and BAT-26) did not detect any mutations, immunohistochemical analysis confirmed the absence of nuclear expression for MLH1 and PMS2, a finding indicative of compromised DNA MMR functionality.

After four cycles of adriamycin/cyclophosphamide, breast MRI showed a decreased tumor to 2.6 cm (partial response by RECIST criteria) (online suppl. Fig. 3b). However, in MRI after docetaxel, a tumor size increase (3.2 cm) was suspected (online suppl. Fig. 3c), and disease progression was confirmed through subsequent surgery with a 3.8 cm tumor and five metastatic lymph nodes (5/12), suggesting ypT2N2a.

Case 4

A 40-year-old woman presented with invasive breast cancer with ER positivity (Allred 4), HER2 positivity, and a Ki-67 index of 54%. The patient had a history of primary and recurrent sarcomas in the right thigh and paraspinal muscles, respectively, 2 decades prior. She received NAC for breast cancer with docetaxel, carboplatin, trastuzumab, and pertuzumab. WGS was performed in parallel to the standard of care.

WGS indicated a 74% tumor cell fraction, mean ploidy of 1.9, 4,531 base substitutions, 1,331 indels, and 395 structural variations. Driver mutations (online suppl. Table S1–3) included ERBB2 amplification (copy number: 23) and PIK3CA (copy number: 10). The germline WGS showed a structurally disrupted TP53 due to complex rearrangements involving genomic insertion of a nuclear mitochondrial DNA segment (NUMT; Fig. 4). LOH of TP53 was confirmed in the cancer genome, suggesting that TP53 inactivation was one of the cancer driver events. Given the TP53 variant, the patient was diagnosed with Li-Fraumeni syndrome, aligning with her sarcoma history. Despite the need for genetic counseling, due to the hereditary risk finding, the patient was lost to follow-up.

Fig. 4.

Complex arrangement of germline TP53 in case 4.

Fig. 4.

Complex arrangement of germline TP53 in case 4.

Close modal

Access to comprehensive data is crucial for oncologists in devising effective treatment strategies. The CancerVision tumor-normal pair method of WGS offers a complete genomic profile, bridging the gaps of conventional testing methods. As “actionable” genetic targets expand with emerging FDA-approved therapies and trial criteria, WGS emerges as an adaptive solution. With falling sequencing costs and advanced bioinformatics capabilities, WGS has transitioned from a research instrument to a vital clinical asset, as demonstrated by its value in breast cancer treatment in this case series.

Luminal-type breast cancer patients undergoing NAC often face low pCR rates (∼10%) with cytotoxic chemotherapy [6], as well as with CDK4/6 inhibitors and endocrine treatments [7]. These rates drive research to identify patients more likely to respond positively through genomic assays. Approximately 5–10% of breast cancers have germline BRCA1/2 pathogenic variants, and an additional 3% of breast cancers carry somatic mutations in the genes [8]. BRCA mutations are associated with treatment responsiveness, especially to therapies like PARP inhibitors and platinum-based drugs [9]. Some studies also indicate that an elevated HRD score, tied to HRR gene mutations, corresponds to enhanced chemotherapy outcomes [4].

In case 1, WGS unveiled two key insights not easily discerned by targeted sequencing: a BRCA2-disrupting somatic structural variation with LOH and a pronounced HRD score pivotal for treatment decision-making. The identification of BRCA2-disruption by somatic structural variations, which were challenging to detect through a targeted panel approach, underscores the necessity of comprehensively understanding all BRCA inactivations. Such understanding could inform chemotherapy responsiveness or guide treatment development like PARP inhibitors.

Furthermore, the traditional HRD calculation method proved to be suboptimal in this context, calling this patient’s tumor HR-proficient. WGS signature-based classification astutely identified it as HR-deficient; coupled with the presence of a BRCA2-disrupting structural variation, this case calls into question the potential limitations of conventional HRD calculations.

Generally, young women with breast and ovarian cancers may indicate hereditary breast and ovarian cancer syndromes, often linked to BRCA mutations. However, some breast cancers may metastasize to the ovaries [10]. Therefore, distinguishing two scenarios (i.e., double primary or metastasis) is crucial for effective treatment.

Case 2 underscored WGS’s capability to equivocally confirm the double primary malignancies, pinpointing no mutual mutations between the breast and ovarian genomes. Furthermore, WGS identified a germline mutation in BRCA1 and concurrent LOH in the genomes of the affected tissue, coupled with the presence of HRD in the mutational signature. These WGS findings corresponded with the patient’s clinical response to NAC using platinum agents. The patient attained a pCR – a noteworthy achievement, particularly in contrast to existing data showing pCR rates of 20–60% for BRCA-linked triple-negative breast cancer [4, 11] and approximately 20% for BRCA-related ovarian cancer [12].

Case 3 highlights WGS’s comprehensive strengths. Although some of the breast cancer patients could benefit from immune checkpoint inhibitors [13], it is inefficient to apply additional MSI testing in all breast cancer due to the low prevalence of MSI in breast cancer. Furthermore, as seen in the patient, traditional RT-PCR-based MSI testing is not sensitive because it examines only a few genomic sites. In contrast, WGS can innately evaluate the MSI status of microsatellite loci genome-wide. WGS provides a complete genomic overview, negating the need for hypothesis-driven test-type selection.

Additionally, while NAC preceded potential immunotherapeutic applications, this case illuminates WGS’s capability to reveal further actionable genomic insights. The detected variants in RB1 and TP53, both linked with LOH, might explain the observed chemoresistance in this case and thereby may have informed alternative treatment approaches.

Guidelines recommend germline genetic testing for personalized cancer treatment and to identify at-risk family members. Yet, a US study found only 6.8% of suitable patients had testing within 2 years post-diagnosis [14]. Merging germline and somatic testing streamlines the diagnostic process, optimizing tissue use and time.

Case 4 illustrates the superiority of a paired-normal WGS approach, revealing a rare genetic anomaly that a tumor-only test would overlook. It identified Li-Fraumeni syndrome, a rare hereditary condition significantly increasing cancer risk. Notably, a unique complex rearrangement variant related to NUMT was found in the germline TP53 gene. NUMTs represent mitochondrial DNA fragments embedded in the nuclear genome over evolution. WGS can detect these uncommon and complex variants effectively [15].

In this study, we showed the strong potential of using tumor-normal paired WGS for precision oncology of breast cancers. As an all-in-one genetic testing method, the approach can deliver comprehensive mutational detection in germline and somatic tissues. Exploring structural variations and mutational signatures is also feasible from WGS-based testing. As multi-dimensional information can be obtained from one test, we believe that it is a cost-effective method for cancer genome evaluation. Further, prospective studies that assess the turn-around time (TAT) of WGS in a real-world clinical setting, another essential factor for its clinical application, will be necessary.

In summary, these cases underscore the clinical utility of clinical-grade WGS in providing comprehensive genome profiling in breast cancer. WGS insights are medically necessary for informing treatment strategies, predicting responses and outcomes, differentiating double primary tumors, and pinpointing germline actionable variants in breast cancers.

Written informed consent was obtained from the patients for publication of the details of their medical case and any accompanying images. The Institutional Review Board (IRB) of Seoul St. Mary’s Hospital approved those studies (KC21TISI0007, KC22TISI0292), and we adhered to the tenets of the Declaration of Helsinki.

The authors have no conflicts of interest to declare except author information on the cover page.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conceptualization: Kabsoo Shin, Ryul Kim, Brian Baek-Lok Oh, Wonchul Lee, Sangmoon Lee, Jeongmin Lee, and Erin Connolly-Strong. Data curation: Ryul Kim, Hansol Park, Wonchul Lee, Sangmoon Lee, Joonoh Im, and Ji Eun Lee. Writing – original draft: Sung Hun Kim, Brian Baek-Lok Oh, Young Seok Ju, and Ji Eun Lee. Writing – review and editing: Kabsoo Shin, Ryul Kim, Brian Baek-Lok Oh, Young Seok Ju, Jeongmin Lee, and Erin Connolly-Strong.

Additional Information

Kabsoo Shin and Ryul Kim are co-first authors with equal contributions.Brian Baek-Lok Oh and Jeongmin Lee are co-corresponding authors with equal contributions.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.

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