In the last few decades, an improved understanding of the molecular mechanisms contributing to breast cancer progression has enabled a more personalized management of the disease. At the Hong Kong Academy of Medicine 25th Anniversary Congress, experts in the field discussed about the latest advances in breast cancer management. Dr. Edmond S.K. Ma of the Hong Kong Sanatorium & Hospital (HKSH) was invited to speak about the use of multigene panel (MGP) testing in cancer management, whereas Dr. Janice W.H. Tsang of the University of Hong Kong (HKU) and Hong Kong Breast Oncology Group (HKBOG) discussed personalized management for breast cancer in 2018 and beyond.
Germline mutations in cancer predisposition genes
Dr. Edmond Ma began his presentation by explaining the concept of precision medicine in oncology. “There is the precision medicine approach, in which the somatic tissue is sent for genomic profiling in an attempt to identify a particular drug target that will predict for the effectiveness of a molecular targeted therapy,” he said. “This approach is, of course, supported by the very affordable cost of next-generation sequencing (NGS) or deep sequencing.”
“But in performing these somatic panels, you should note that these panels would also include genes that have a germline predisposition to cancer risk,” Dr. Ma continued his explanation. “[Therefore], we would also encourage a peripheral blood sampling to pair with the cancer tissue for better germline filtering.”
Of note, to promote standardized reporting of actionable information from clinical genomic sequencing, the American College of Medical Genetics and Genomics (ACMG) has published a minimum list of genes to be reported as secondary findings during exome or genome sequencing. This list now includes 59 genes, as per the latest version of the recommendations (ACMG SG v2.0).1
Issues regarding the clinical actionability of mutations
NGS-based MGP has enabled a higher capacity to analyze genetic variance, but Dr. Ma noted the frustration of using it as a reflex testing. Referring to the study on 1,303 high-risk patients (negative for BRCA1, BRCA2, TP53 and PTEN) who were selected from Hong Kong Hereditary Breast Cancer Family Registry (HKHBCFR), 61 (4.68%) pathogenic or likely pathogenic variants, which correspond to 12 different cancer predisposition genes, were identified via NGS panel for 30 genes.2 With a 29% of variants of unknown significance (VUS) found,2 this also denotes the challenge to interpret the clinical significance of such findings. “Genetic counselling, both pre- and post-test, is very important,” Dr. Ma said.
“I think the important message is that not all genes included in MGP are necessarily clinically actionable,” he explained, while referring to the availability of direct-to-consumer genetic testing. “MGP is [now mainstream], we have to accept that. It’s for us to decide how best to utilize it or reduce the caveats or limitations.”
Advances in HER2-positive breast cancers
Dr. Janice Tsang began her presentation by highlighting the milestones of anti-human epidermal growth factor receptor 2 (HER2) therapies in breast cancer over the past four decades. “We are predicting that maybe in the next 10 or 20 years, we will not be classifying cancers as primary from breast or lung, but maybe [as] HER2 or EGFR [cancers],” she said.
Bearing in mind the approval of trastuzumab in 2006 as the first adjuvant treatment of HER2-positive breast cancers,3 the field has continued to advance rapidly with the most recent update from the phase 3 KATHERINE trial, which was presented at the 2018 San Antonio Breast Cancer Symposium (SABCS).4
A substantial improvement in invasive disease-free survival was seen with the use of ado-trastuzumab emtansine as compared to trastuzumab (HR=0.50; 95% CI: 0.39-0.64) in patients with early-stage breast cancer with residual invasive disease after receiving neoadjuvant chemotherapy and trastuzumab.4,5 The findings of KATHERINE were published in The New England Journal of Medicine.5
Dr. Tsang, however, believed that there are still many unanswered questions for HER2-positive diseases. In terms of “matching science with affordability”, the use of trastuzumab as an adjuvant treatment continues to be explored. For example, Tolaney et al. explored the use of adjuvant paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy in HER2-positive patients with tumors measuring up to 3cm in greatest dimension.6 Although the study findings failed to support the use of such regimens in all patients with small HER2-positive tumors, the authors concluded that paclitaxel plus trastuzumab may be an acceptable treatment approach for low-risk HER-positive breast cancers.6
Advances in HR-positive breast cancers and TNBC
For adjuvant endocrine therapy in hormone receptor (HR)-positive breast cancers, the benefits of 5-year tamoxifen have been confirmed since the 1970s.7 Continuous investigations for adjuvant tamoxifen or aromatase inhibitors were performed by trials such as ATLAS, MA.17R, and SALSA, but Dr. Tsang noted that there is still an unmet need for biomarkers in HR-positive diseases. “We only know that there are [high-risk patients] who would benefit a bit more from a longer duration [of hormone therapy], but that’s balancing against the cost of drug and toxicities like osteoporosis,” she said.
Exciting developments were also seen with the triple-negative breast cancers (TNBC). Instead of having just chemotherapy as the treatment option, median progression-free survival (PFS) was significantly longer with the addition of the anti-programmed death-ligand 1 (anti-PD-L1) atezolizumab to nab-paclitaxel in the phase 3 IMpassion130 trial.8 The median PFS was 7.2 months with the combination and 5.5 months with chemotherapy alone (HR=0.80; 95% CI: 0.69-0.92; p=0.0025).8
“For BRCA1 or BRCA2 mutations, which are encountered in about 20% of all TNBC, we now have the PARP (poly[adenosine diphosphate-ribose] polymerase) inhibitor with olaparib as one of the prototypes,” Dr. Tsang explained.
Knowledge gaps in the era of precision medicine
Dr. Tsang then discussed about the situation in Hong Kong, taking into consideration the increasing proportion of elderly patients living/diagnosed with breast cancers. “With the use of the additional genomic assays, not only you could spare patients from chemotherapy, but for elderly, perhaps to particularly identify those with high-risk who could benefit from chemotherapy,” she said. “Age should not deter intensive treatment, as alluded by the SIOG (International Society of Geriatric Oncology) guidelines.”
Before ending her presentation, Dr. Tsang described some of the existing gaps in the era of precision medicine such as inter-patient heterogeneity, intra-tumor heterogeneity, and the lack of validation for the current multigene signatures to predict endocrine treatment efficacy. “We must use multidisciplinary team management. It’s always not a single decision, but across multiple disciplines with different experts,” she said.
In line with the theme of the anniversary congress, which is “Beyond 25: New Paradigms in Healthcare”, continuous advancements in personalized breast cancer management have been made in the last few decades. There remain many unanswered questions about what the future holds in the field of breast cancer, but important steps have been taken toward the right direction.
1. Kalia SS, Adelman K, Bale SJ, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19(2):249-255.
2. Kwong A, Shin V, Au CH, et al. Multigene panel testing for hereditary breast and ovarian cancers: An analysis of 1303 BRCA-negative Chinese patients. J Clin Oncol. 2018;36(suppl):e13625.
3. FDA Approves Herceptin for the Adjuvant Treatment of HER2-Positive Node-Positive Breast Cancer. Genentech Media Releases. 2018 (Accessed December 20, 2018, at https://www.gene.com/media/press-releases/10207/2006-11-16/fda-approves-herceptin-for-the-adjuvant-).
4. SABCS 2018: KATHERINE Trial: Adjuvant Ado-Trastuzumab Emtansine vs Trastuzumab in Early-Stage HER2-Positive Breast Cancer. The ASCO Post. 2018 (Accessed December 19, 2018, at http://www.ascopost.com/News/59541).
5. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2018 [Epub ahead of print].
6. Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015;372(2):134-41.
7. Jordan VC. Tamoxifen as the first targeted long-term adjuvant therapy for breast cancer. Endocr Relat Cancer. 2014;21(3):R235-46.
8. Roche’s Tecentriq in combination with Abraxane improves outcomes as an initial treatment for people with PD-L1-positive metastatic triple-negative breast cancer. Roche Media Release. 2018 (Accessed December 20, 2018, at https://www.roche.com/media/releases/med-cor-2018-10-20.htm).