Adapting to the Changing Treatment Landscape in Early Breast Cancer

The treatment landscape for early breast cancer (EBC) is rapidly expanding thanks to recent FDA approvals for abemaciclib and pembrolizumab and positive trial data for olaparib in the adjuvant setting. Below, I share my thoughts on how to incorporate these agents into the clinic, along with the open questions and dilemmas surrounding their use.

Moving Targeted Therapies Into the Adjuvant Setting: HR-Positive, HER2-Negative Disease
Given the well-established benefits of CDK4/6 inhibitors in metastatic hormone receptor (HR)–positive, HER2-negative disease, many healthcare professionals were puzzled and disappointed when the PALLAS and PENELOPE trials both found no benefit with palbociclib in the adjuvant setting. Indeed, the first positive data for CDK4/6 inhibitors in early-stage disease came from the monarchE trial, which demonstrated that adjuvant abemaciclib plus endocrine therapy (ET) significantly improved invasive disease-free survival. The FDA subsequently approved adjuvant abemaciclib plus ET for patients with HR-positive, HER2-negative EBC that is lymph node positive, at high risk of recurrence, and with a Ki-67 score ≥20%.

We are now challenged to identify which patients belong to this high‑risk EBC population eligible for adjuvant abemaciclib. It is straightforward to identify patients with ≥4 positive lymph nodes but evaluating those with 1‑3 lymph positive lymph nodes deemed to be high risk is more difficult. The ASCO and NCCN guidelines base their recommendations for adjuvant abemaciclib on the patient characteristics of the intent-to-treat group from monarchE whereas the FDA approval is only for those patients with HR-positive, node-positive EBC at the highest risk of recurrence as defined by a high Ki-67 score of ≥20%. Ki-67 has long been established as a prognostic biomarker in breast cancer but plagued by heterogeneity in its assessment leading to the FDA approval of a companion diagnostic for abemaciclib with the advantage of standardizing many features of this assay to address Ki-67 analyses. We must determine whether Ki-67 should be assessed upfront for all patients with HR-positive, HER2-negative breast cancer, which can also aid in identifying luminal A and B HER2-positive tumors or limit testing only to those tumors that are HR positive, HER2 negative, and node positive. For tumors where the Ki-67 expression is close to but not quite meeting the somewhat arbitrary Ki-67 ≥20% cutoff (eg, 18%-19%), I retest, especially in the presence of other high-risk features, such as tumor grade or tumor size.

Moving Targeted Therapies Into the Adjuvant Setting: BRCA-Mutant Disease
Regarding use of PARP inhibitors in early disease, a key development came when the OlympiA trial demonstrated that adjuvant olaparib significantly prolonged invasive disease-free survival vs placebo in patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative, high-risk EBC. The OlympiA study population consisted largely of patients with triple-negative breast cancer (TNBC) but included a smaller subgroup (<20%) with HR-positive, HER2-negative disease, drawing our attention to the potential benefits of PARP inhibition in this setting.

With these options now available in EBC, how do we best use a shared decision-making approach to individualize therapy choices for our patients? Currently, I am caring for a patient with BRCA-positive, HR-positive locally advanced disease. Although she had a great response to neoadjuvant therapy, a small amount of residual disease was noted at the time of surgery. When considering how to proceed with both olaparib and abemaciclib as possible options, we discussed the magnitude of benefit of adjuvant therapy with olaparib, abemaciclib plus ET, and ET alone. On the one hand, the OlympiA data are compelling for the BRCA-positive EBC population; on the other hand, olaparib has the potential for significant toxicities including nausea, anemia, neutropenia, and fatigue that can be challenging for the patient who is just recovering from surgery and prior chemotherapy. I assured my patient that if she discontinued the PARP inhibitor due to intolerance, abemaciclib plus ET was another option with the same magnitude of benefit, albeit accompanied by different toxicities. She could also pursue ET alone to minimize the need for additional toxicity monitoring and clinic visits.

However, the benefits of adding olaparib or abemaciclib to ET are meaningful and merit beginning therapy with consideration of dosing modifications and/or supportive care medications as needed. The key is shared decision-making with the patient—in this case, making the patient aware of the reduction in risk of recurrence and the magnitude of benefit these agents confer, and that it is also OK to stop therapy if the adverse events are deemed unmanageable and discuss the other available treatment options. Yet, I have had other patients who, after discussing the risks and benefits of adding these targeted agents to standard adjuvant ET, are not interested in the small magnitude of absolute benefit these agents provide with the addition of the burdens these targeted agents can impose on daily life—and I respect their choice. Most patients will initiate therapy albeit with a lower threshold of discontinuation when encountering toxicities or the need for additional supportive care medicines to manage these toxicities. Data on how to best sequence these targeted therapies options in the adjuvant setting are eagerly awaited.

Using Immunotherapy for Early TNBC
Based on positive results from the KEYNOTE-522 trial, pembrolizumab received FDA approval in 2021 for patients with high-risk, early TNBC as neoadjuvant treatment in combination with chemotherapy and continued as monotherapy in the adjuvant setting.

Healthcare professionals are now also charged with the task of identifying the patients most likely to benefit from immunotherapy, paired with the risk of immune-related adverse events, some of which may be permanent. Educating patients on the merits and challenges of the addition of immunotherapy to standard chemotherapy is of paramount importance. I am currently treating a young patient with neoadjuvant pembrolizumab, and she noted her increasing fatigue—certainly not uncommon in a patient undergoing taxane and anthracycline-based chemotherapy. It turns out that she had developed profound hypothyroidism because of the immunotherapy component of her treatment likely compounded by the cumulative fatigue from her chemotherapy and was subsequently given thyroid replacement therapy. One basis of identifying patients appropriate for neoadjuvant immunotherapy is tumor size: KEYNOTE-522 enrolled patients who had tumors 1-2 cm in diameter if there was nodal involvement or >2 cm regardless of nodal involvement. Would a patient with a 1.8-cm tumor really be less likely to benefit? Personally, I look for every reason to give neoadjuvant immunotherapy for TNBC. Another issue involves PD-L1 status, an established criteria for immunotherapy in metastatic TNBC. However, the approval of pembrolizumab in early TNBC is not dependent on PD-L1 status, but analyses showed a higher pathologic complete response rate and improved event-free survival in those with PD‑L1–positive vs PD-L1–negative disease. At my institution, the testing panel for early TNBC includes PD-L1 status so this can quickly be incorporated in later treatment decisions and recommendations. Given that large proportions of patients with early TNBC are candidates for neoadjuvant therapy, we then have that information if the patient progresses to metastatic disease, where the FDA indication for pembrolizumab requires a PD-L1 combined positive score ≥10. However, for many of these patients, I will rebiopsy a metastatic site and retest for PD-L1 status.

Current Questions and Challenges

Testing
Now that data show benefit with adjuvant olaparib, to whom with early-stage breast cancer should we offer germline BRCA testing outside of those with strong family histories? The NCCN guidelines clearly address which patients with TNBC should be tested—but what about those with HR-positive disease, which represents the majority of breast cancer and a small patient population subset in the OlympiA trial? We may be missing eligible patients with HR-positive disease who lack a strong family history suggestive of a germline BRCA mutation. Do we now offer all patients with HR-positive breast cancer testing or establish an age appropriate cutoff as in patients with TNBC without family histories? Again, the goal is to continue to best identify those patients with EBC who may benefit from the addition of olaparib. This is partnered with how already challenged healthcare professionals can best take on additional patient screening and genetic testing for germline mutations, especially amid the COVID-19 pandemic when resources, including genetic counselling, are sparse. Currently, my approach is to take it on a case-by-case basis for patients with HR-positive disease, given that the OlympiA data show us that many of these patients should be offered testing so as to not miss the identification of patients that potentially may benefit from olaparib.

Furthermore, it can be overwhelming to patients to discuss genetic testing at the time of discussing a new diagnosis and treatment of their breast cancer, particularly in light of the potential impact genetic testing results may have on appropriate surgery decisions. This is coupled with the potential need for family disclosures, including the challenging circumstance of facing the possibility and guilt of passing a genetic mutation on to their children and those subsequent repercussions. Personally, I introduce the concept and role of genetic testing at the initial consultation and acknowledge that we will continue to address and discuss it in more depth at subsequent follow-up visits, giving those patients additional time to process the implications of genetic testing not only for themselves but also their family and allowing them to focus on processing their breast cancer diagnosis. A neoadjuvant treatment strategy can also facilitate bifurcation of the immediate need for treatment decisions and treatment initiation from the challenges of informed consent for genetic testing, recognizing the importance of the potential role of obtaining these results prior to surgery decisions.

When should we evaluate Ki-67 for patients with EBC, given the benefits of abemaciclib in very high-risk disease? For the patient I discussed above, I had to specify that I wanted her Ki-67 score assessed on her initial biopsy specimen, not on her residual disease specimen. Her neoadjuvant therapy may have effectively eliminated the proliferative clone of cells potentially manifesting a higher Ki-67 score and more likely to be responsive to neoadjuvant chemotherapy leaving the more indolent breast cancer population which may manifest lower Ki-67 scoring.

Sequencing and Combining Therapies
Because PARP and CDK4/6 inhibitors are so new to managing early-stage breast cancer, we have no data yet on whether there is incremental benefit in sequencing these agents and how best to sequence them or whether we can combine them. Ongoing trials are evaluating combinations of these agents but have yet to read out.

Who Benefits From CDK4/6 Inhibitors?
There is an ongoing debate about why the PALLAS trial was negative for palbociclib whereas the monarchE trial was positive for abemaciclib: Was it the higher-risk disease, node-positive disease requirement with Ki-67 criteria in monarchE? The nonstop twice-daily continuous dosing schedule? Broader mechanism of action targeting CDK4 more than CDK6 while also hitting CDK2 and CDK9? We may get some more answers from the ongoing NATALEE trial, which is evaluating a reduced dose of adjuvant ribociclib plus ET administered for 3 years, in contrast to the 2 years in PALLAS and monarchE, in patients with HR-positive, HER2-negative EBC, including node-negative and node-positive disease.

Treatment Fatigue
It is clearly challenging for patients to be on an adjuvant regimen for several years that causes fatigue and/or requires regular laboratory assessments and monitoring, especially after following chemotherapy, surgery, radiation, and so on. This is particularly true now during the pandemic and with the increasing requirements of patients to juggle and oversee children who are now often at home learning remotely. We must recognize that these therapies do incrementally improve outcomes, but they come with a price of financial, physical, and emotional costs and that the potential benefits may not outweigh the risks for some patients, particularly if they have lower risk of recurrence.

Final Thoughts
These are all good challenges to have as we tease out the subsets of patients who will continue to benefit most from these new approaches and work through the challenges of how to best incorporate appropriate molecular marker testing into our clinical practice. Shared decision-making is increasingly important with additional treatment options and analyzing the risks and benefits for each patient. Now more than ever shared decision-making entails more discussions to best provide our patients with the required tools and platforms to make the optimal choices for patients with EBC.

Your Thoughts?
Do you routinely test your patients with EBC for BRCA mutations, Ki-67, and PD-L1? Please share your thoughts in the discussion section.