Symposium Overview

The 44^th Annual San Antonio Breast Cancer Symposium (SABCS) 2021 was its first hybrid meeting. In the following symposium overview, discover:

• Dynamic genetic profiles in breast cancer tumours
• Clinical trial updates
• Summaries of the two plenary sessions

View Article 2 - HER2+ and Brain Metastases

View Article 3 - Novel HER2+ Therapies and Clinical Updates

View Article 4 – SABCS 2021 Interview with Professor Nadia Harbeck 

Symposium Overview

Top highlights from SABCS 2021

Even in light of the COVID-19 pandemic, progress continues to be made in understanding the genetic heterogeneity of breast cancer and the role of metabolism in tumour progression. Importantly, we have learnt that the genetic profile of tumours is dynamic, and the need for individualised treatment regimens cannot be overemphasised.

Understanding the mechanisms behind tumour metabolism have advanced our knowledge of endocrine therapy resistance in HER2, FGFR and other RTKs. “Elucidating the molecular features of sensitivity and resistance to CDK4/6 inhibitors may ultimately lead to the identification of predictive biomarkers and new therapeutic strategies,” Dr Christina Curtis said (Stanford University).

Significant findings were presented to support escalating therapy in high‑risk and de‑escalating in low‑risk early breast cancer patients¹. The approval of pembrolizumab plus chemotherapy (early TNBC) and abemaciclib with endocrine therapy (high‑risk ER+) have improved outcomes. “We need to think about how we might use other biomarkers to guide patient selection for further chemotherapy-free trials in HER2-positive disease while maintaining or increasing the pathologic complete response (pCR) rates and survival and minimising toxicities,” Dr Foluso Olabisi Ademuyiwa said (Washington University School of Medicine).

Advances in the management of advanced metastatic breast cancer included data from new antibody‑drug conjugates (ADCs), sacituzumab, and trastuzumab deruxtecan (T‑Dxd) versus trastuzumab emtansine (T‑DM1). Evidence of overall survival in ER+ metastatic disease following CDK4/6 inhibitors continues to show benefits, although there is a high need for new targets to overcome endocrine resistance.

Updates were provided on clinical trials for HR+ early breast cancer, where adjuvant use of CDK4/6 inhibitors have shown conflicting results between the PALLAS² and monarchE³ studies. Meta-analyses of aromatase inhibitors (AI) show advantages in distant disease recurrence, especially for those with high‑risk disease, but tolerability remains a big issue.

The importance of menopausal status is reflected in women with HR+/HER2- early breast cancer, where a 44–46% reduction was seen when chemotherapy was added to endocrine therapy in pre-menopausal women. Still, no benefit was seen in post‑menopausal women. In an exploratory analysis, the use of metformin found an unexpected benefit in HER2+ cancers that were not seen in other cancer types, which requires further exploration.

The event-free survival benefits of neoadjuvant/adjuvant pembrolizumab were highlighted in results from the KEYNOTE-522 trial for triple‑negative breast cancer (TNBC). The greatest benefit was in patients with pathologic complete response (pCR).

Plenary 1: Genomic profiling in early ER‑positive breast cancer

In the first of the Plenary Sessions, Professor Mitch Dowsett from the Royal Marsden Hospital, London, presented data on the genomic profiling in early ER-positive breast cancer.

Microarray analysis confirms that ER+ breast cancer has hierarchical clustering of gene expression giving molecular portraits of breast cancer with a continuum between the intrinsic subtypes: Basal-like, HER2 enriched, Luminal A, or Luminal B. From core-cut biopsies taken at diagnosis and surgery two weeks later, with no treatment in between, it was found that 25% were discordant. Therefore, two biopsies can give different results and hence a different diagnosis.

Analysis of the activity of the 50 genes known as the PAM50 gene signature showed that Luminal A subtypes had lower risk and better outcomes. The clinical utility of genetic profiles is also complicated as different commercial screens produce different results. Oncotype Dx is dominated by oestrogen signalling and Prosigna^® by proliferation.

The Peri-Operative Endocrine Therapy—Individualising Care (POETIC) trial⁴ in post-menopausal women with ER+ early breast cancer showed that the oestrogenic environment does affect gene transcription, but oestrogen has little biological response among ER/ESR1 low tumours. Immune signalling in ER+ tumours were related to poorer response to endocrine treatment rather than better, but the mechanism is unclear.

The common TP53 mutation has a strong prognostic significance above some molecular profiling tests. There are multiple pathways of endocrine resistance related to immune signalling, but various types of immune cells are involved.

Professor Dowsett also warned of artefacts in transcriptional profiling that may give false responses.

Plenary 2: Lisa Carey TNBC pitfalls and progress

Dr Lisa Carey, from the University of North Carolina, Chapel Hill, presented the pitfalls and progress in TNBC, for which there are currently no treatment targets, and few fit into the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) I/II categories.

While breast cancers are less immune-activated than other tumours, TNBC has the highest immune activation of the BCs. Tumour infiltrating lymphocytes (TILS) vary widely but are prognostic in chemotherapy and treatment-naïve TNBC and are predictive of chemotherapy benefit. Methods other than TILS to define immune activation include PD-L1 immunostains, gene expression signatures, RNA expression, and immune cell clonality assays.

A prospective study indicated that TNBC patients were younger and had a higher stage of diagnosis, primarily high‑grade. Interestingly, the study revealed that young African women were three times more likely to have TNBC than older Caucasian women. While relapse rates have decreased due to better chemotherapy, relapse is more common in TNBC than other subtypes but falls off around year 5.

Dr Carey also presented data from the KEYNOTE-522 trial⁵ that were practice‑changing, showing that pre-surgery neoadjuvant chemotherapy (NAC) in combination with chemotherapy were more likely to have a pCR. In patient’s ineligible for breast conservation (BCS), 42% converted to breast conservation after NAC. Of those having BCS, 80% were successful. Overall, she concluded that while data from this study are encouraging, new management strategies are required for early TNBC.

Join us for our next SABCS 2021 highlight article which explores HER2+ breast cancer and brain metastases

HER2+ and Brain Metastases 

References

1. Pérez-Garcia JM, Guerror-Zotano Á, Medioni J, Schneeweiss A. A phase 2 study of chemotherapy de-escalation using a pathological response- guided strategy in patients with HER2-positive, low-risk early breast cancer: PHERGain-2. Presented at the San Antonio Breast Cancer Symposium, 7–10 December 2021. Poster OT1-12-07.
2. Gnant M, Dueck AC, Frantal S, Martin M, Burstein H, Greil R et al. Adjuvant palbociclib in HR+/HER2- early breast cancer: Final results from 5,760 patients in the randomized phase III PALLAS trial. Presented at the San Antonio Breast Cancer Symposium, 7–10 December 2021. Abstract GS1-07.
3. Goetz MP, Gonzalez Trujillo JL, Toi M, Huober J, Llombart-Cussac A, Zhang W et al. Abemaciclib plus fulvestrant or nonsteroidal aromatase inhibitor in participants with HR+, HER2- breast cancer - A pooled analysis of the endocrine therapy-naïve participants with measurable disease in MONARCH 2 and MONARCH 3. Presented at the San Antonio Breast Cancer Symposium, 7–10 December 2021. Poster P1-18-21.
4. Lopez Knowles E, Detre S, Hills M, Schuster GF, Cheang MCU, Tovey H et al. Estrogen receptor expression thresholds by IHC and mRNA for Ki67 response to aromatase inhibition: A POETIC study. Presented at the San Antonio Breast Cancer Symposium, 7–10 December 2021. Poster PD15-06.
5. Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kümmel S et al. KEYNOTE-522: Phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early-stage high-risk triple-negative breast cancer (TNBC). Presented at the San Antonio Breast Cancer Symposium, 7–10 December 2021. Abstract GS1-01.