Breast cancer highlights from ASCO 2019

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Published: 6 Jun 2019
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Dr Matteo Lambertini - San Martino Hospital, Genoa, Italy

Dr Matteo Lambertini speaks with ecancer at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting about the conference highlights in breast cancer research.

He first discusses results from two studies in the metastatic HER2-positive setting, the SOPHIA trial and the NALA trial, before going on to discuss two studies in hormone receptor positive metastatic breast cancer, the MONALEESA-7 trial and a Korean trial investigating whether it's better to start with chemotherapy or endocrine therapy.

Dr Lambertini then reports findings from an international, retrospective study that he presented on the safety of pregnancy following breast cancer in patients with a BRCA mutation.

He concludes by discussing the GeparOLA and the GIM4 trials.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

At ASCO 2019 we had some important presentations in both the metastatic and early setting. We started discussing the data in the metastatic setting where we have four important presentations, two in the HER2 positive disease and two for the hormone receptor positive disease. We started discussing the HER2 positive abstract, these are two randomised trials, the first that I’m going to discuss is the SOPHIA trial and the second one is the NALA trial. Both of these abstracts are related to, as mentioned, metastatic HER2 positive disease and both of them in patients with heavily pre-treated metastatic HER2 positive disease.

In the SOPHIA trial the authors investigated the efficacy of margetuximab. This is a new monoclonal antibody, anti-HER2, which has some differences as compared to trastuzumab which is the current standard of care beyond the third line setting for these patients. This is a monoclonal antibody that has been engineered so that the FC portion is more effective than the one of trastuzumab. This was a randomised trial in which patients received chemotherapy, four different types of chemotherapy, our standard of care in this setting with trastuzumab or with margetuximab. So it was a head to head comparison between these two agents. Almost 600 patients were randomised and the study met its primary endpoint, so the progression free survival was statistically significant in favour of the margetuximab arm with a hazard ratio of 0.76, so a 24% reduced risk of progressing with the use of margetuximab as compared to trastuzumab in this, as mentioned, heavily pre-treated population. But in terms of absolute number there was only one month improvement in progression free survival with no major differences in overall survival. So we probably need more mature data maybe to see with more mature data if we can have also some signal of efficacy in terms of overall survival because, as mentioned, it’s a heavily pre-treated population so we need to see some signal of benefit also in terms of overall survival. In terms of toxicity profile there were no major differences as compared to trastuzumab but again we need more mature data to really comment on the efficacy of this agent.

The second trial in the HER2 positive setting is the NALA trial. This is again, as mentioned, a randomised trial in the heavily pre-treated population in which the authors compared capecitabine plus lapatinib, one of the current available options beyond the third line for patients with HER2 positive disease to capecitabine plus neratinib. The main difference is this is a TKI, tyrosine kinase inhibitor, with the major difference as compared to lapatinib is that this is a pan-HER inhibitor and it’s a near reversible inhibitor. So these are the two main differences as compared to lapatinib.

The study, as the prior trial, met its primary endpoint showing a statistically significant improvement in progression free survival with a hazard ratio that was exactly the same as the prior study, 0.76. However, as in the prior trial, we could not see any signal in terms of overall survival and response rate. We have to mention that in terms of toxicity profile neratinib was associated with a higher rate of diarrhoea, almost 25% of the patients, it was almost doubled than the rate observed with capecitabine and lapatinib which is the current standard of care in this setting.

Moving now to the hormone receptor positive metastatic breast cancer, here again there are two trials that I would like to discuss. Both of them are for patients, for premenopausal women, and both of them address the role of CDK4/6 inhibitors. The first is the MONALEESA-7 trial, this is a large randomised trial in premenopausal patients, endocrine sensitive disease, that were randomised to receive endocrine therapy alone or endocrine therapy plus ribociclib. We know the PFS data – almost a 10 month improvement in PFS, this was already previously reported and published but here at ASCO the authors reported updated results and specifically overall survival results. This is actually the first randomised trial investigating CDK4/6 inhibitors that shows a clearly statistically significant benefit in overall survival. I think these are very important data that reinforce once again the indication to use these agents as the preferred first line treatment in this specific setting.

The second study that I wanted to discuss, again in premenopausal patients with luminal-like breast cancer, is the Korean trial in which the authors tried to address one of the questions that we always have in our clinic – is it better to start with endocrine therapy or is it better to start with chemotherapy in such a patient population? So the authors randomised almost 200 premenopausal patients to receive capecitabine single agent or endocrine therapy with exemestane plus ovarian function suppression and palbociclib, so endocrine therapy plus targeted agents versus chemotherapy.

The trial showed that the combination of endocrine therapy and targeted therapy is actually superior to chemotherapy with an almost 8 month improvement in progression free survival. So this is the proof of what is already endorsed by guidelines, that in patients with hormone receptor positive advanced disease we have always to start with endocrine therapy with or without targeted agents before moving to chemotherapy, of course in patients that do not have a visceral crisis and do not need to start chemotherapy right away.

Moving now to the early setting I wanted to start with a study that we presented that is very important for young women with germline BRCA mutations. In this study we investigated the safety of having a pregnancy in patients with a prior risk of breast cancer and carrying a germline BRCA mutation. This is an issue of great importance because still a lot of physicians believe that having a pregnancy in women with a prior risk of breast cancer can be contraindicated, should probably not be considered safe. However, we have several data in the overall breast cancer population but not a lot of data to counsel our BRCA mutated breast cancer patients.

In this study, this was an international hospital-based retrospective cohort study, we were able to include more than 1,250 premenopausal patients all diagnosed under the age of 40 and all of them carrying a germline BRCA mutation. 195, so approximately 16% of the total population, had a pregnancy after the end of treatment, so following breast cancer diagnosis. The two main take home messages are that, first, we could not observe any detrimental effect on the prognosis of the patient. So disease free survival and overall survival of patients with a pregnancy following breast cancer was the same, or actually the DFS even better, for those who had a pregnancy following breast cancer. The second important information is that we did not have any alarming signal in terms of safety for the baby so that the rates of spontaneous abortion, congenital malformation as well as pre-term delivery were highly comparable to those that we expect in the healthy general population.

So this is an important study to counsel our young BRCA mutated breast cancer patients about the safety of future conception and also the possibility to receive fertility preservation strategies and pregnancy should not be contraindicated any more, of course after an adequate treatment and period of follow-up.

Regarding other oral presentations in the early setting a very interesting study was the GeparOLA trial in which the authors randomised patients to taxane anthracycline based chemotherapy agents, our current standard of care as neoadjuvant treatment for this type of patients, and the randomisation was between adding carboplatin to taxane based chemotherapy versus olaparib. So a head to head comparison between a PARP inhibitor and a platinum agent in the neoadjuvant setting for patients with HER2 negative, HRD, hormonal recombination deficient, tumours. The result was that there was no significant difference in terms of pathologic complete response between the two options with just a signal of a slightly higher rate for the olaparib group that was mostly observed in patients with HRD defective tumours without germline BRCA mutation. This setting appeared to be more effective olaparib.

The other study for women with hormone receptor positive disease was the GIM4 trial. This is an Italian study that investigated the efficacy of extended adjuvant endocrine therapy with an aromatase inhibitor, in this case it was letrozole. This trial randomised patients after 2-3 years of Tamoxifen to continue the treatment up to five years with letrozole or to continue up to 7 years, so five more years of letrozole. The study showed that actually extended treatment with letrozole appeared to be associated with a better disease free survival with a borderline statistically significance, approximately 3% absolute benefit in disease free survival at three years, suggesting that this can be considered an option for patients with hormone receptor positive disease that we believe are at higher risk of disease recurrence and need extended adjuvant endocrine therapy.