CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Nurses: 1.00 Nursing contact hour
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 27, 2023
Expiration: March 26, 2024
In this module, 7 multidisciplinary experts—medical oncologists Banu Arun, MD, and Charles E. Geyer, Jr., MD; breast surgeon Emilia Diego, MD, FACS; pathologist Constance Albarracin, MD, PhD; nurse practitioner Marissa Marti-Smith, MSN, APRN, AGNP-C, AOCNP; clinical pharmacy specialist Allison Butts, PharmD, BCOP; and genetic counselor Kristen Shannon, MS, CGC—discuss the importance of BRCA testing and the role of adjuvant olaparib in early breast cancer.
Please note that the slide thumbnails in this activity link to a PowerPoint slideset supplementing the discussion by the faculty. This slideset may be downloaded by clicking on any of the thumbnails within the activity.
Clinical Care Options plans to measure the educational impact of this activity. A few questions will be asked twice: once at the beginning of the activity, and then once again after the discussion that informs the best choice. Your responses will be aggregated for analysis, and your specific responses will not be shared.
Before continuing with this educational activity, please take a moment to answer the following questions.
Banu Arun, MD:
Breast cancer remains a major health problem among women, not only in the United States, but also worldwide.1 During the past 20-30 years, we’ve had the opportunity to dissect some of the etiologies, particularly regarding genetics, and we now know that approximately 10% to 15% of all breast cancers are related to either high-penetrant or intermediate- to low‑penetrant genes.2 Although the rest is still genetic—what we used to call sporadic—they’re most likely due to single-nucleotide polymorphisms and environmental interactions and some other very low–penetrant genes. With the advent of implementing clinical cancer genetics into clinical practice testing, the introduction of improved screening, and personalized therapies for breast and other cancers (eg, PARP inhibitors for prostate and pancreas cancer), there is now a huge intersection of risk assessment, genetics, and cancer treatment.
Cancer genetics and cancer treatment are increasingly converging because of the major implications of genetic testing results for patients. These genetic test results can personalize both screening for cancer and treatment and may affect family members as well. In this discussion, we will dissect elements of this new era of genetics and cancer, focusing mainly on the role of BRCA testing and adjuvant olaparib in early breast cancer in a multidisciplinary fashion.
Constance Albarracin, MD, PhD:
Management of patients with breast cancer begins with an evaluation of estrogen receptor (ER), progesterone receptor (PgR), and HER2, the primary prognostic and predictive markers in breast cancer. The goal of the pathologist is to provide an accurate assessment of these markers following American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines that have been refined over time. ER/PgR immunohistochemistry (IHC) assays are scored based on percentage of invasive tumor cells with nuclear staining: negative (0%), low positive (1%-10%), or positive (>10%).3
The intensity of staining is also reported and should be evaluated in the context of tissue controls. In cases of low or faint intensity, comparison with appropriate positive control can avoid a false positive result. In cases of negative ER/PgR, the presence of a positive control is relevant to ensure that the assay was successful. The guideline updates have resulted in standardizing specimen handling and analysis as well as evaluation of the tests. Information on these parameters is now a necessary component of the report.
Similarly, the evaluation for HER2 has been evolving. In the 2018 ASCO/CAP guidelines, HER2 evaluation is based on results from on IHC or fluorescence in situ hybridization testing.4 In our institution, HER2 testing starts off with IHC stains and samples are scored as negative (0, 1+), equivocal (2+), or positive (3+). Equivocal cases are further evaluated for gene amplification by in situ hybridization. In our institution, we use a double-probe in situ hybridization assay and evaluate the results based on 3 parameters. These include the ratio of HER2 to centromere 17, the number of HER2 signals/cell, and the number of CEP17 signals/cell. In general, HER2 is negative when the ratio of HER2/CEP17 signals is <2.0 and HER2 signals/cell are <4.0. HER2 is amplified when the ratio is ≥2.0 and HER2 signals/cell are ≥4.0. The analytic tests as well as the interpretation of both the IHC and in situ hybridization are challenging. Validation of testing conditions, as well as proficiency tests, are underway to assure accurate results.
Ki67 is an important tumor marker in breast cancer that has been used in clinical trials to define pathologic response and compare drug efficacies. In contrast to ER/PgR and HER2, there are no well-defined guidelines for Ki67 as to specimen handling, assays, and interpretation of test results.5,6
Although IHC stains are commonly used to assess Ki67, quantitation is limited by lack of standard scoring methods. The International Ki67 in Breast Cancer Working Group has proposed counting 100 cells across 4 areas of varying Ki67 density and taking the average.6,7 An alternative method is selecting representative areas of “hot spots,” which have the highest Ki67 nuclear labeling, for quantitation. Most commonly, the total percentage of Ki67 in the entire tumor is quantified visually or by digital analysis. This remains the most common method of choice for Ki67 assessment in our clinical practice.
Charles E. Geyer, Jr., MD:
Oncologists have employed routine assessment of ER/PgR and HER2 for more than 2 decades, and substantial efforts by the pathology and diagnostic communities have resulted in a high degree of accuracy and reproducibility of the assays used to classify breast cancers into the major subtypes which guide therapy. In the HR‑positive/HER2-negative subtype, gene expression profile classifiers have been developed that provide important additional information for prognosis and treatment planning. Testing for pathogenic variants in germline BRCA1, BRCA2, and PALB2 is now also part of the initial evaluation of patients with early onset breast cancer, a strong family history of breast or ovarian cancer, or the triple-negative subtype of breast cancer.
Banu Arun, MD:
Pathology is really the key here. For patients with HR-positive disease, the treatment landscape is getting more complicated; I think pathology is very important not only for the testing indications, but also for treatment modality and sequencing.
Constance Albarracin, MD, PhD:
Germline testing for BRCA uses gene sequencing technology. Usually, we receive the results within 7-14 days, which is important when we are planning the patient’s surgery or treatment with a PARP inhibitor. Results are categorized as benign variants, variants of uncertain significance, or as pathogenic/likely pathogenic variants.
Banu Arun, MD:
As discussed above, the tumor’s molecular characteristics could help in decision-making. Therefore, pathology reports are important in reporting ER/PgR and HER2 status of the tumor. Furthermore, based on the criteria for adjuvant olaparib treatment in the OlympiA trial, both measurable residual disease and pCR need to be described in pathology reports.
Kristen Shannon, MS, CGC:
It is important to note that the word “mutation” has historically been used in the cancer genetics space when talking about genetic test results. Technically, the word “mutation” means only that there is a change or variation in the DNA sequence of a gene. It does not describe the pathogenicity of the DNA change. That is, it does not clarify if the DNA change is pathogenic (disease causing, or a “positive” result), neutral/polymorphic (not disease causing, or a “negative” result) or unclear in pathogenicity (uncertain, or unknown result). Culturally, however, the word “mutation” has a negative connotation that leads to the inaccurate assumption that all mutations are pathogenic or disease causing. To standardize and clarify the language of genetic test reporting, the American College of Genetics and Genomics decided to retire the term “mutation” and use the word “variant” instead, as “variant” seems culturally impartial.8 Since “variant” is a noun, it requires an adjective to describe the impact of the variant further. Hence, the current 5 classifications of variant exist: pathogenic variant, likely pathogenic variant, variant of uncertain significance, likely benign variant, benign variant.
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