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Introduction
The World Health Organization (WHO) defined genomics as the study of genes and their functions, and related techniques (WHO, n .d.). The completion of the Human Genome Project (HGP) in 2003 marked a new era of the genome in medicine and health. Although our knowledge of human genomes is far from complete, genomics is making a huge impact on health and disease. The advances in genome sequencing technology and analysis are opening up a new window on cancer progression, informing new approaches to diagnosis and treatment across the disease pathway (Hill, 2018). In this paper, the author takes breast cancer patient treatment management as an example to refute the statement that genomics adds nothing new to what we have already known. From the application of breast cancer preventative screening programs, and molecular stratification of breast cancer, to the precision medicine of the right drug and right dose for the right patient based on the genomic profile, the potential benefits of genomics to breast cancer care are enormous.
Genomics applied to breast cancer prevention
There are about 20-30% of breast cancer patients have a family history and only 5-10% of these patients have gene mutations (Caso et al.,2017), but the identification of these mutations plays a significant role in guiding patients in risk-reducing interventions and surveillance protocols. Genomic testing provides a unique opportunity for individualized cancer risk prediction. Early detection and intervention potentially decrease the morbidity and mortality of breast cancer.
Breast cancer (BRCA) gene screening and risk prediction tools
According to the World Cancer Research Fund (WCRF) (2017), breast cancer is the most common cancer in women worldwide. Although mammography screening programs have been established worldwide. However, as age is the only risk to be considered for women to have mammograms, the one size fits all screening recommendation may not be effective and beneficial for all. Louro et al. (2019) conducted a systematic review and assessed the quality of individualized breast cancer risk prediction tools used in the studies up to February 2018, they identified four models to predict breast cancer risk, namely the Breast Cancer Risk Assessment Tool (BCRAT), the Breast Cancer Surveillance Consortium (BCSC), the Rosner and Colditz model, and the International Breast Cancer Intervention Study (IBIS). Even though it is hard to recommend any of the models as the standard tool for predicting individual risk, from the first publication of the BCRAT model in 1989 till the time of the study, genetic variation was updated in all of the models to improve the quality and accuracy of the tool. Although the BRCA genes were discovered in the 1990s, they didnt attract much attention from the public until Angelina Jolie revealed herself to be the carrier of a BRCA1 gene mutation on 14 May 2013 (Troiano et al., 2017). She underwent a prophylactic mastectomy and laparoscopic bilateral salpingo-oophorectomy as her estimated risk of developing cancer was 87%. Angelina Jolies disclosure of BRCA status led to a big increase in BRCA tests with a peak of +80%. Narods 2010 study (as cited in Troiano et al., 2017) revealed that the vast majority of inherited breast cancers are due to mutations of the genes BRCA1 and BRCA2. Women who carry these highly penetrant genes have a lifetime risk of breast cancer of 50%-85% compared to 5%-10% in males (Shiovitz & Korde, 2015). The information about BRCA mutation assists the patients and family members in taking preventive measures. These measures include risk-reduction surgeries such as mastectomy and salpingo-oophorectomy, chemoprevention medicine tamoxifen and raloxifene, and intensive screening (Tyler, 2019). Bilateral mastectomies have shown a remarkable decrease in mortality for women who carry inherited genes of BRCA1 and BRCA2 with early-stage cancer (Caso et al., 2017).
BRCA genes test in Australia
Cancer Australia (n. d.) recommended the genetic testing of BRCA1 and BRCA2 gene mutations for women diagnosed with breast or ovarian cancer, regardless of their age and family history. On 12 October 2017, Australia Broadcast Corporation (ABC) announced the breaking news of the BRCA gene test free for patients at high risk of breast and ovarian cancer (Scott, 2017). The free gene testing has been claimed as a huge milestone while one in eight women will develop breast cancer before the age of 80 in Australia. Breast Cancer Network Australia (BCNA) also welcomed the news of Medicare rebates for genetic testing (BCNA, 2017), the rebates not only improve womens access to genetic testing but the timely information will help them to make the right intervention decision. As BRCA genes are familial, the genetic test is also funded for relevant family members in Australia. This funding policy has reduced the financial burden on the patients and their families. The genetic testing result also assists the family members in seeking a further medical diagnosis of breast cancer, and the early recognition of hereditary breast cancer is crucial in clinical management.
Genomic testing in cancer stratification and prognosis
Traditionally, breast cancer was classified simply by its histological appearance and its origination (Makki, 2015). The non-invasive breast cancers are ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), which are confined to the ducts and lobules and potentially malignant. Whereas, invasive breast cancers including invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and metastatic breast cancer have invaded the stroma. Such morphological categorizations are inadequate for precision medicine in individualized patient treatment.
Molecular subtypes of breast cancer and their roles
The whole-genome analysis by using a genome-wide association study (GWAS) and next-generation sequencing (NGS) advanced cancer genome profiling study (Low et al., 2017). To provide information on breast cancer prognosis and treatment planning, the identification of molecular subtypes of breast cancer through the genomic technology of immunohistochemistry and gene expression profiling becomes a critical component (Fragomeni et al., 2018). The four molecular subtypes of breast cancer include luminal A, luminal B, and human epidermal growth factor receptor2 (HER2)-positive and basal-like. Luminal A is estrogen receptor (ER)/ progesterone receptor (PR) positive and HER2 negative and accounts for 50% of invasive breast cancers (Makki, 2015). Patients in this group benefit from endocrine therapy such as tamoxifen and aromatase inhibitors with good prognosis (Fragomeni et al., 2018). In the subtype of luminal B, the ER/PR is positive and HER2 is variable. The prognosis is poorer compared with luminal A as the response to endocrine therapy and chemotherapy is variable (Makki, 2015). From the definition of HER2 positive, the ER/PR is usually negative and HER2 is strongly positive in this group. The patients in this group showed the highest sensitivity to HER2-targeting drugs such as trastuzumab and pertuzumab (Makki, 2015). Basal-like is a morphologically, genetically, and clinically heterogeneous category of breast cancer and is associated with unfavorable prognosis (Fragomeni et al., 2018). As ER, PR, and HER2 are all negative in the subgroup of basal-like, it is also called triple-negative breast cancer (TNBC). Tumors with the BRCA1 mutation fall into this subtype and show a high histologic grade.
The role of genomics in breast cancer etiology and pathogenesis
Cancer is the most common genetic disease that results from the accumulation of genetic alterations (Low et al., 2017). Germline alterations can be inherited as they are found in germ cells whereas somatic are cellular alterations. Somatic alterations are acquired during a persons lifetime and are accounted for by most breast cancers. The BRCA1, BRCA2, CYP2D6, and fibroblast growth factor receptor2 (FGFR2) are examples of germline mutations identified by using the technology of GWAS, NGS, and genetic linkage analysis. PIK3CA, TP53, GATA3, and PTEN are the somatic mutations that were uncovered in luminal breast cancer through the genomic technology of targeted re-sequencing, whole-exome sequencing (WES), or whole-genome sequencing (WGS). The identification of patients who are predisposed to the high risk of breast cancer by investigating germline mutations and the exploration of molecular portraits of breast cancer by analyzing somatic mutations potentially aid in individualized patient care.
Genomic Applied to Breast cancer treatment and Precision Medicine
Precision medicine also called personalized medicine, is defined by the National Institute of Health (NIH) as an approach to patient care that allows doctors to select treatments that are most likely to help patients based on a genetic understanding of their disease (NIH, 2017). The eradication of tumors from the breast and regional lymph nodes and preventing metastatic recurrence for non-metastatic breast cancer as well as prolonging life and symptom palliation for metastatic breast cancer are the two principles of therapy for breast cancer patients (Waks & Winer, 2019). The decision-making for individualized patient care is also based on several factors including tumor morphology, grade classification, presence of lymph node metastases, and genomic expression of ER, PR, and HER2 (Fragomeni et al., 2017). Furthermore, the individualized treatment plan relies on the understanding of prognostic and predictive biomarkers.
Genomics applied in the early stage breast cancer treatment
Traditionally, the early stage breast cancer treatment includes surgery and chemotherapy. As germline variants play an important role in the choice of treatment and the prediction of therapeutic effectiveness, the approach to breast cancer treatment has changed. In the study of Wockel et al. (2018), the treatment with denosumab in BRCA1 mutation showed promising results, the adjuvant use of tamoxifen in premenopausal women is also one of the effective treatments, and the treatment with aromatase inhibitors becomes the standard practice in postmenopausal patients with breast cancer. Hamdan et al. (2019) found that adjuvant chemotherapy has a significant reduction in the risk of metastatic relapse in patients with ER-positive, and HER2-negative without lymph node involvement. The discovery of the 21-gene expression assay served as a valuable prognostic and predictive biomarker for patients who received hormonal therapy (Wockel et al., 2018). To provide the right dose for the right patient, the discovery of variants on the enzyme CYP2D6, which activates tamoxifen by pharmacogenomics study has reduced the drug-induced adverse event (Low et al., 2017).
Genomics applied to the treatment of HER2-positive breast cancer
Apart from the surgery intervention, neoadjuvant and adjuvant chemotherapy regimens may be considered. To be able to make the right therapeutic decision, the detection of HER2 status in the primary tumor or metastatic samples has been suggested by Hamdan et al. (2019). The neoadjuvant therapy can be administered to patients if the postoperative chemotherapy is indicated (Wockel et al., 2018).
Genomics applied to the treatment of TNBC
The treatment of TNBC is very challenging owing to the lack of hormonal receptor expression and HER2 amplification, therefore, chemotherapy remains the first-line treatment choice (Low et al., 2017). Makki (2015) revealed that most of the high-grade invasive breast cancers belong to this molecular subtype and the prognosis is poor. However, studies demonstrated that breast cancer patients with BRCA1 mutations are very sensitive to chemotherapy with platinum agents such as cisplatin and carboplatin (Godet &Gilkes, 2017). According to Hammerl et al. (2017), this type of breast cancer may benefit from immunotherapy because TNBC bears the highest number of T cells.
Genomics applied to surgical treatment of breast cancer
The risk-reduction prophylactic mastectomy surgery has shown a 90% decrease in the lifetime risk of breast cancer (Caso et al., 2017). The blood-based biomarkers such as circulating tumor cells (CTC), and circulating tumor deoxyribonucleic acid (ctDNA) that are released from the primary tumor may indicate the metastases (Low et al., 2017). The test of these biomarkers can be used as an early indication of the presence or recurrence of breast cancer to guide surgical treatment.
Conclusion
The rapid evolution of genomic technology has reshaped the approach to breast cancer treatment. Genomics has had a notable influence on breast cancer prevention, cancer molecular subtype stratification, identification of gene mutations, and personalized treatment. Cancer care will be modified in the future while there are 40 rare disease and cancer flagship projects from Australia Genomics evaluating the clinical utilities of different sequencing modalities, including WGS, whole-exome sequencing (WES), ribonucleic acid(RNA) sequencing, and large capture panels in Australia (Stark et al., 2019). The contribution of genomics in breast cancer care is enormous and will magnify in the future. In conclusion, the statement that genomics adds nothing new to what we have already known is incorrect.
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