In breast cancer, neoadjuvant endocrine therapy shows promise in a variety of areas, including as an excellent testing platform, Ingrid A. Mayer, MD, MSCI, said in a presentation during the 2019 Lynn Sage Breast Cancer Symposium.
Ingrid A. Mayer, MD, MSCI
In breast cancer, neoadjuvant endocrine therapy shows promise in a variety of areas, including as an excellent testing platform, Ingrid A. Mayer, MD, MSCI, said in a presentation during the 2019 Lynn Sage Breast Cancer Symposium.1
Neoadjuvant endocrine therapy allows clinicians to determine resistance mechanisms to endocrine therapy with or without targeted agents. It also allows for the development and triage of novel combinations of endocrine therapy with targeted agents, and helps prioritize certain arms in adjuvant and metastatic phase III trials, as well as validating biomarkers, she said.
Mayer, the Ingram Professor of Cancer Research and co-leader of the Breast Cancer Program at Vanderbilt University Medical Center, summarized current uses for neoadjuvant endocrine therapy. It has traditionally been considered appropriate for elderly or frail patients or those with a short life expectancy who either cannot have surgery or should not delay it. Additionally, neoadjuvant endocrine therapy is effective in luminal A—like cancers, including lobular cancers and hormone receptor (HR)–positive cancers with low Ki67 and high expression of estrogen receptors (ERs) and progesterone receptors.
However, clinicians should be using neoadjuvant endocrine therapies in a variety of additional clinical and mechanistic ways, explained Mayer. Clinically, these therapies may be helpful in reducing tumor size preoperatively, which can lead to improved surgical outcomes, she said. Additionally, they may increase the number of patients who achieve a pathological complete response (pCR) when given for an extended duration.
“Clinical trials with short duration of neoadjuvant endocrine therapy may have underestimated the true potential of pCR as an endpoint,” she said.
Another use of neoadjuvant endocrine therapy is to interrogate biomarkers of response and mechanisms of resistance in post-treatment residual cancer, which can lead to the development of mechanism-based treatments for endocrine therapy—resistant disease, Mayer said.
For example, whole-genome analysis can inform whether a patient with HR-positive breast cancer will respond to aromatase inhibition.
“MAPK pathway alterations are good prognostic features and TP53 mutations are bad prognostic features,” she noted.
In a study that examined whole-exome/RNA sequencing in HR-positive breast cancer and response to aromatase inhibition, she noted that ESR1 fusion transcripts were associated with resistance to estrogen therapy and CCND1 and FGFR1 amplification are associated with resistance to estrogen deprivation.2
Neoadjuvant endocrine therapies may also be instrumental in identifying patients with HR-positive disease who can safely forego adjuvant chemotherapy, thanks to Ki67 status and genomic signatures. Additionally, Preoperative Endocrine Prognostic Index (PEPI) scores, which use surgical tumor characteristics following neoadjuvant endocrine therapy to predict outcomes in patients with HR-positive breast cancer, may indicate which patients can safely omit chemotherapy.
Moreover, In Mayer’s opinion, genomic signatures may work just as well in the neoadjuvant setting, but more validation is needed.
“However, PEPI score and Ki67 assessment at 2 weeks are clinically validated endpoints that could be ready for day-to-day practice,” she said, adding that there are some caveats. “The analytical validation and standardization of Ki67 interpretation must be achieved and intra-tumoral heterogeneity must be accounted for. And, drugs that cause apoptosis versus proliferation arrest need to be accounted for as well.”
Additionally, neoadjuvant endocrine therapies may provide insight into the biologic basis of the efficacy of both ER and non-ER—targeting agents, Mayer said.
“Ki67 at 2 weeks consistently predicts long-term outcomes of endocrine therapy with targeted therapy in both the adjuvant and metastatic setting,” she said. “We have the opportunity to use neoadjuvant endocrine therapy as a much more abbreviated testing ground for novel endocrine/targeted therapy combinations and to ‘pick the winners and tease out the losers’ to move forward to large phase III trials in the adjuvant or metastatic setting.”
For example, Ki67 was utilized in the phase II neoMONARCH trial, which looked at neoadjuvant therapy with the CDK4/6 inhibitor abemaciclib (Verzenio) plus anastrozole in patients with HR-positive/HER2-negative early-stage breast cancer. Results showed that the combination induced complete cell cycle arrest, which was the study’s primary endpoint, as measured by Ki67 for 67.8% of patients.3 For those treated with abemaciclib alone, cell cycle arrest was achieved for 57.7% of patients; for those who received anastrozole alone, 14.3% of patients experienced cell cycle arrest.
Finally, Mayer presented the audience with a schema with multidirectional flow that showed her ideal clinical deployment of neoadjuvant endocrine therapy. For example, at diagnosis of HR-positive/HER2-negative stage I to III breast cancer, the workup should include Ki67 and genomic signatures. These should be repeated 2 weeks into the first therapy cycle to predict outcomes in the adjuvant or metastatic setting and to help inform more relevant clinical trial design.
At both initial diagnosis and the 2-week mark, Ki67 can also identify patients who may or may not benefit from adjuvant chemotherapy. A 6-month course of neoadjuvant endocrine therapy would be given either alone or in conjunction with a targeted agent. Other agents may be needed as well, if the Ki67 is greater than a 10% concentration.
After the 6-month course, interpretation of the PEPI score, recurrence score. and genomic signatures can lead to biomarker validation and discovery of mechanisms of drug resistance.