Day Three – Tailoring HER2+ treatment and real-world CDK4/6 inhibitor data

Day Three – Tailoring HER2+ treatment and real-world CDK4/6 inhibitor data

By Heather Mason

Tailoring treatment for HER2+ early breast cancer

Aleix Prat summarised studies for tumour and immune-related gene/signatures that predict pathological complete response (pCR) in the biologically heterogeneous HER2+ population¹⁵. The CALGB40601 trial evaluated 688 RNA biomarkers showing that 31% were associated with pCR. Still, only 7% were associated with RFS; concluding that the pathology which drives prognosis is different to the pathology that drives pCR. This may explain the lack of relationship between increasing pCR rates with new drugs and improvements in survival.

The IgG immune signature is indicative of an adaptive immune response. However, a combined analysis of CALGB40601 and PAMELA trials that compared immune gene signatures with tumour-infiltrating lymphocytes (TILs) found a moderate correlation. In fact, 11 immune signatures were mostly B-cell-related, and these outperformed TILs for pCR prediction. An 8-gene signature to predict trastuzumab survival benefit showed only 10% of HER2+ patients benefited from trastuzumab. Therefore, on-treatment biology could help identify patients who are candidates for de-escalation or escalation treatment strategies.

Valentina Guarneri describes a neoadjuvant platform to personalise treatment for HER2+ eBC, identifying patients needing treatment escalation or de-escalation to optimise the cure rate¹⁶. Escalating post-neoadjuvant therapy in patients with residual disease from the KATHERINE trial and high-risk populations (DESTINY-Breast05, CompassHER2RD) provided data on strategies to enhance pCR rates. Similarly, de-escalating neoadjuvant therapy with anthracyline-free regimens (TRAIN-2 trial, TRYPHENA trials) showed similar pCR and survival responses. Omitting chemotherapy in the neoSPHERE trial also provided a pCR, justifying the neoadjuvant approach for de-escalation.

Models for predicting pCR rates need optimising by selecting patients based on biomarkers

In the perELISA trial, patients with HER2+/HR+ disease were selected based on the Ki67 response after two weeks of letrozole. pCR rates according to PAM50 selection were 45% overall, and 66.7% according to the combined biomarker HER2E/ERBB2 high mRNA.

Hee Jin Lee discussed the early prediction of pCR by molecular analysis¹⁷. Results from the I-SPY2 trial showed a significant correlation between HER2 high amplification and pCR. HER2 heterogeneity (found in 10% of tumours) can also be used as a biomarker. Heterogeneity, particularly in the fraction of ERBB2, was a strong predictor of treatment resistance. This study also found that a lack of ctDNA clearance was a significant predictor of poor response and recurrence. In contrast, ctDNA clearance was associated with improved survival even if pCR was not reached. In patients with a HER2 enriched subtype, patients treated with T-DM1 had higher pCR than those with basal-like or luminal tumours. Data from the NOAH trial, PAM50 analysis found a 10-gene signature model for predicting pCR rates after neoadjuvant trastuzumab therapy. Combined analysis of seven studies evaluating the chemo-endocrine score (CES) found that a high CES was associated with a lower probability of achieving pCR, independent of clinical characteristics, therapy, and subtype.

Philip Poortmans presented data on the locoregional approach to managing HER2+ BC¹⁸. HER2+ is usually undetectable until around ten years old. Today, pCR rates are between 50–70%. Local breast conservation therapy is considered standard, and local recurrence rates are 2.56% in T1-2NO-1 stage BC (2020 data). Omitting post-mastectomy radiation therapy (RT) has a much higher risk of recurrence. Very recent Danish data shows 33 years of follow up data that has no increase in non-BC related mortality. ESROACROP recommends only partial radiation in favourable subtypes, but not in HER2+ patients. De-escalation of RT in patients with T1N0 HER2+ patients leads to a nearly 4-fold increase in mortality risk. De-escalation can, however, be achieved in HER2+ patients by hypofractionation of 5 fractions over one week. Some patients require more RT. The HERA trial found that RT boost did not improve local control other than in younger patients <40 years of age. RT and survival is an interaction between surgery and systemic therapies. In conclusion, the extent of surgery can be decreased after primary systemic therapy after a good response (same for RT).

Lessons from real-world data

This session presented European real-world data.

Sandra Geurts presented data from the SONABRE register following the implementation of new systemic therapies for advanced breast cancer (n ≥ 5000) (2007 to date)¹⁹.

Since the implementation of pertuzumab and T-DM1 in 2013 for patients with HER2+ metastatic BC, the overall survival of patients in 2019 was not significantly different in HR+/HER2+ patients. Still, for HR-/HER2+ patients, a significant improvement in OS of 18 months was observed following the introduction of pertuzumab/T-DM1. This was due to lower uptake of pertuzumab/T-DM1 in HR+/HER2+ patients, who had a higher uptake of ET therapy.

The use of CDK4/6 inhibitors (since 2017) in patients with HR+/HER2- MBC was analysed. At 2-year after diagnosis, 50% of patients received CDK4/6 inhibitors. The data showed that CDK4/6 is the preferred second-line therapy, which aligns with Dutch guidelines, but not international recommendations, and that ET use could still be decreased.

While the RWE provided valuable mirror information, there was a mismatch between clinical experience and RWE. RWE is quickly outdated.

Real-world evidence contributes evidence on the effectiveness of holistic patient care, and for identifying predictors of attrition

Filippo Montemurro presented RWE on patient attrition across lines of treatment for metastatic disease. The GIM-14 platform collects data from patients undergoing first-line treatment for MBC, with the primary objective to analyse therapy types according to subtype²⁰.

Attrition data is important in clinical practice, as it estimates the possibility that a patient on treatment may be unable to receive a second treatment upon regression. In GIM-14, patient attrition was lower than reported in RCTs. Predictors of first-to-second line attrition were: age, menopausal status, stage at diagnosis, tumour subtype, and short term benefit from first-line treatment. First-to-second line attrition was found to be only 7.1% in patients with HER2+ BC.

Andreas Hartkopf introduced the German PRAEGNANT registry, which stores data on clinical data, molecular characteristics, patient-reported outcomes, treatments, and adverse events from 4,704 patients with MBC²¹. RWE complements the evidence of RCTs, as RCTs are slow, lack external validity, with little data on late events, which is essential in oncology.

The data shows a shift in chemotherapy use from first- to second-line therapies following CDK4/6 inhibitors. After CDK4/6 was approved by EMA, German authorities did not accept this approval based on the PFS data. Therefore, the community collected PRAEGNANT data to show that disease progression has a negative impact on QoL.

Germline mutation analysis revealed that 4.6% of HR+/HER- MBC patients and 13.4% of the TNBC population harbour the BRCA 1/2 MBC, which is the target for PARP inhibition. Therefore, irrespective of family history, every patient should be offered germline testing.

Real-world evidence shows major improvements in overall survival in patients with HER2+

Thomas Grinda presented on the ESME project, which is a data platform combining patient, treatment, and hospital databases²². Large scale data sets are required in RWE to minimise the potential for bias. Since 2008, ESME has data from over 30,000 consecutive patients with MBC, 19.2% are HER2+, 65.2% are HR+/HER2-, and 14.3% are TNBC.

From 2008 to 2017, the median OS was 50.1 months for HER2+, 43.3 months for HR+/HER2-, and 14.8 months for TNBC. In this time period, the proportion of de novo MBC has increased significantly in the HER2+ subgroup than in other subtypes. This may be due to more patients being cured at the localised stage, or improved sensitivity of diagnostic tests for better initial staging in all subtypes. Receipt of newly released treatments may explain differences in OS according to subtype.

References

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