ASCO 2022 Meeting Report — Breast Cancer

The 2022 American Society of Clinical Oncology (ASCO) annual meeting, held in Chicago June 3–7, highlighted important advances in cancer research. Here, Editor-in-Chief Dr. William Gradishar focuses on key trials in breast cancer. Meeting abstracts can be viewed in the ASCO meeting library.

By far the most impactful presentation at ASCO 2022 was DESTINY-Breast04, reported by Modi and colleagues (abstract LBA3). Previously, the decision to use HER2-targeted therapy in either the early or late stage was based on a binary decision: HER2-positive or HER2-negative. HER2-positive status was defined as immunohistochemistry (IHC)2+ if fluorescent in situ hybridization (FISH)-positive or IHC3+ (with or without ISH testing). Although nuances to test interpretation have been defined by the ASCO-CAP guidelines, the essential decision was straightforward for most patients. Any case that fell outside of these parameters was not considered an appropriate candidate for HER2-directed therapy.

Now, results from the industry-sponsored, randomized, phase 3 DESTINY-Breast 04 trial will allow clinicians to broaden the population of patients who are candidates for HER-directed therapy with the antibody–drug conjugate trastuzumab deruxtecan (T-DXd).

Patients with HER2-low (IHC1+, or IHC2+ and ISH negative) metastatic breast cancer refractory to endocrine therapy and 1 or 2 lines of prior chemotherapy for advanced disease were randomized 2:1 to T-DXd or physician's choice of treatment (gemcitabine, capecitabine, eribulin, paclitaxel, or nab-paclitaxel). Of 557 patients, approximately 90% were ER-positive and of these, two thirds received a prior CDK4/6 inhibitor.

The primary endpoint, progression-free survival, was a median of 9.9 months in the T-DXd arm versus 5.1 months in the physician's choice arm (P<0.0001). Results were similar in the subset of patients with ER-positive disease. A statistically significant improvement in overall survival was also seen in patients receiving T-DXd (median, 23.4 vs. 16.8 months; P=0.001). Although the subset of patients with HER2-low/ER-negative disease was small, similar trends in progression-free survival and overall survival were observed. The objective response rate was also three times higher in patients receiving T-DXd. No new safety signals were identified, and the rate of drug-induced interstitial lung disease remained low in those receiving T-DXd.

This trial will change the way advanced breast cancer is treated. The population in this study would typically receive single-agent chemotherapy, but identifying patients defined as HER2-low opens another option with superior efficacy: T-DXd. National Comprehensive Cancer Network guidelines have already been updated to reflect T-DXd as an appropriate option for patients who would have met the entry criteria to DESTINY-Breast04.

Read more about the study in the New England Journal of Medicine and watch an interview with the study's lead author.

The question of whether sequential use of CDK4/6 inhibitors confers clinical benefit in metastatic ER-positive/HER2-negative breast cancer has been debated and the approach occasionally tried in clinical practice, but trials addressing this clinical issue have been lacking. The first trial to explore this question, the randomized, phase 2, industry-sponsored MAINTAIN trial, was reported by Kalinsky and colleagues (abstract LBA1004).

Patients with ER-positive/HER-negative metastatic disease who received ≤1 line of chemotherapy for advanced disease and had disease progression on endocrine therapy and any CDK 4/6 inhibitor were randomized to receive ribociclib or placebo and to switch their endocrine therapy (from fulvestrant to exemestane, from any other agent to fulvestrant). The primary endpoint was progression-free survival.

Of 119 patients, 86% had received prior palbociclib and the median duration of prior CDK4/6 exposure was approximately 16 months. Only 9% of patients had received chemotherapy for metastatic disease. Progression-free survival was significantly improved from a median of 2.76 months without ribociclib to 5.29 months with it. The fraction of patients without disease progression at 6 and 12 months was also greater for those receiving ribociclib. An exploratory analysis of progression-free survival in fulvestrant recipients and exemestane recipients showed the addition of ribociclib improved progression-free survival with either agent. In another exploratory analysis, the benefit of adding ribociclib appeared to be limited to patients with ESR1 wild-type disease, whereas there was no benefit in those with ESR1 mutations.

This is the first trial showing a potential clinical benefit to switching to a different CDK4/6 inhibitor after disease progression on another CDK4/6 inhibitor. The fact that the endocrine therapy was also changed at disease progression brings another variable into these results. Several other trials are addressing this issue and results will likely be reported in the next year.

Just as it has become a priority to identify patients in whom systemic adjuvant therapy can be de-escalated without compromising outcome, similar efforts have been undertaken for local therapy. Whelan and colleagues reported findings from LUMINA, a prospective, multicenter, single-arm trial evaluating omission of radiation therapy after breast conserving therapy for low-risk, T1N0 breast cancers (abstract LBA501).

Using a combination of clinical and pathological factors and molecularly defined intrinsic subtypes, investigators identified a group of patients with a particularly low risk of local recurrence (age ≥55 and disease characterized as T1N0, nuclear grade 1–2, and luminal A subtype, defined as ER ≥1%, PR >20%, HER2-negative, and Ki67 ≤13.25%). Patients with multifocal or multicentric disease, extensive ductal carcinoma in situ, or lymphatic-vascular invasion were excluded. All patients were to receive adjuvant endocrine therapy and were not offered radiotherapy. The primary endpoint was local recurrence, either noninvasive or invasive.

Of 505 patients, mean age was 67 years, approximately half had tumors 1.1–2.0 cm in size, and two thirds had grade 1 tumors. Adjuvant endocrine therapy consisted of tamoxifen in 41% and an aromatase inhibitor in 59%. At 5 years a total of 10 local recurrence events occurred, for a 5-year recurrence rate of 2.3%. This low rate was below the boundary of 5% set at the outset of the study.

The investigators estimated that in North America alone, 30,000 to 40,000 women meeting this study's criteria could safely avoid adjuvant radiation therapy.