Treatment holidays most likely to be safe for HER2-positive and/or hormone receptor-positive advanced breast cancer

Treatment holidays, where therapy is temporarily stopped, are something that those living with advanced breast cancer sometimes have to contemplate. Perhaps there is an important occasion coming up – a wedding or other family celebration, or an overseas trip – where the side effects of the treatment would interfere with enjoyment of the occasion. In discussing this with their oncologist, it’s important to take into account the current evidence – for or against – taking treatment holidays.  

Here's BCAC’s report of a talk on this topic at the recent ABC7 international advanced breast cancer conference:

Treatment holidays most likely to be safe for HER2-positive and/or hormone receptor-positive ABC
Dr Joseph Gligorov, Paris, France

According to the World Health Organisation, health is “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity”. On this basis, oncologists must consider three ‘protagonists’ when deciding whether it is in the patient’s best interests to implement a treatment holiday:

1.    Disease: extent; symptoms; biology; prognosis. These guide our decisions regarding treatment.
2.    Treatment: effectiveness; tolerability; duration; expectation regarding the treatment.
3.    Patient: most importantly, what does the patient want? What is the risk vs the benefit? How much confidence does the patient have in the decision?

Snapshot of recommendations on treatment holidays

HER-2 positive disease transformed by trastuzumab, pertuzumab, and trastuzumab deruxtecan

Treatment with docetaxel, trastuzumab and pertuzumab resulted in 20% of patients with no disease progression at 5 years, and 16% with no progression at 8 years [1]. Patients who do not relapse after the first 1 to 2 years are less likely to relapse as time goes on. With trastuzumab deruxtecan 55% of patients had no disease progression after 2 years of treatment [2]. In patients with de novo disease (ABC that is diagnosed at the same time as the primary breast cancer), three factors make it less likely for a patient to relapse after a treatment holiday: age less than 65 years; having a complete response; trastuzumab treatment for more than 2 years [3].

HR-positive/HER2-negative benefit from CDK4/6 inhibition – but not HER2-low

Here we discuss median progression-free survival (PFS) in months (median PFS = the time point at which 50% of patients will have progressed and 50% will not)
•    For patients taking aromatase inhibitors as their first treatment, the median PFS is 15–16 months [4]
•    With CDK4/6 inhibitors, median PFS is expected to be 24 months when they are given as first-line treatment, and around 12 months as second-line treatment [4].

These results may be enough to consider treatment holidays in these patients – but now we need to consider trastuzumab deruxtecan and HER2-low ABC. In patients with HR-positive and HER2-low ABC, treatment holidays may not be recommended; even though trastuzumab deruxtecan improves PFS in these patients, the benefit is not as marked as in HER2-positive disease, and so we need to keep treating.

A Japanese study assessed the effect of stopping all endocrine treatment in HR-positive/HER2-negative ABC: the results showed that time to progression is shorter when you are doing this at second-line treatment stage. Therefore, it is better to introduce treatment holidays early on in this population [5].

Triple negative ABC – maintenance treatment but not holidays yet

With pembrolizumab, some patients with triple negative ABC can remain stable for up to 2 years – compared with several months prior to introduction of this drug. This applies to people with the PD-L1 mutation [6]. Olaparib produces similar results in patients with a germline BRCA mutation [7]. However, in triple-negative disease, we are talking about maintenance rather than treatment holidays.

In summary, treatment holidays are most likely to be possible with HER2-positive ABC in patients with a complete response. However, as Dr Gilgorov concluded, it isn’t just about treatment, because caring for others is... “also about helping them to achieve their goals. If the aim of stopping treatment is to allow a life project and the disease progression profile suggests that this is possible, then we have a moral duty to respect patients’ wishes.”

References

1.    Swain SM, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Apr;21(4):519-530. doi: 10.1016/S1470-2045(19)30863-0.
2.    Hurvitz SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 2023; 401 (10371): 105-17
3.    Kaplan HG, et al. Trastuzumab therapy duration in HER2-positive de novo metastatic breast cancer: 1999-2018.Breast Cancer Res Treat. 2022 Sep;195(2):171-180. doi: 10.1007/s10549-022-06678-1.
4.    Munzone E, et al. Systematic review and meta-analysis of post-progression outcomes in ER+/HER2− metastatic breast cancer after CDK4/6 inhibitors within randomized clinical trials. ESMO Open. 2021 Dec; 6(6): 100332.
5.    Morita M, et al. Optimal Treatment of Hormone Receptor-positive Advanced Breast Cancer Patients With Palbociclib. Anticancer Res. 2023 Jun;43(6):2783-2789. doi: 10.21873/anticanres.16447.
6.    Cortes J, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020; 396, (10265): 1817-28. 
7.    Senkus E, et al. Olaparib efficacy in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer: Subgroup analyses from the phase III OlympiAD trial. Int J Cancer. 2023;153(4):803-814. doi: 10.1002/ijc.34525.Epub 2023 Apr 6.

Marion Barnett

29 November 2023