This patient is a 58-year-old woman who presented with stage II breast cancer that was estrogen receptor [ER]positive and HER2-negative, with an intermediate recurrent score. She was treated with anastrozole [Arimidex] alone in the adjuvant setting. At the end of her 5 years of anastrozole, she was found to have liver metastasis. This is a bit of an unusual scenario for a woman with an invasive lobular cancer; it says to me that there must have been some component of more aggressive disease in there, such as a pleomorphic invasive lobular cancer. This probably explains, in my mind, why she developed the liver metastasis. But now she has metastatic breast cancer and is going to need a treatment option for her metastatic disease.

This 58-year-old woman presented with an invasive lobular cancer that was a T2N0 breast cancer, ER-negative, HER2-positive. I would have sent an Oncotype recurrent score for her as was done; it came back at 19. Fortunately, because of the TAILORx trial data, we have excellent high-level evidence that she will not benefit from chemotherapy. The postmenopausal women in the midrange recurrent scores really had no benefit at all from chemotherapy. We can sit down and say with a good degree of certainty that we would recommend antiestrogen therapy alone, and aromatase inhibitor would be ideal for her. I would also treat her with intravenous zoledronic acid every 6 months for 5 years per our new National Comprehensive Cancer Network [NCCN] Guidelines. We have very clear-cut evidence that she will not benefit from chemotherapy.

This case is unusual because the recurrent score was in the reassuring range; it was 19. And we would feel that the antiestrogen therapy, the anastrozole, would have a high degree of benefit for her, assuming she was adherent to the treatment. It&rsquo;s a bit unusual to develop liver metastasis at the end of the aromatase inhibitor period of 5 years. She must have had an aggressive component in there, some pleomorphic invasive lobular cancer; certainly, it&rsquo;s important to biopsy that disease and make sure that there wasn&rsquo;t a subclone that was HER2-positive, for example. Assuming that the liver was biopsied and is the same breast cancer, estrogen receptor&shy;positive, HER2-negative, we then think about treatment options for her. It&rsquo;s very clear to me that a CDK4/6 inhibitor with endocrine therapy would be the definite standard of care for her, and this is something that we would talk to her about. In the older years, we would have considered chemotherapy for metastatic breast cancer in the liver, and she is somewhat symptomatic with that. But now with the CDK4/6 inhibitors, we know that she&rsquo;ll get superior outcomes with CDK4/6 inhibitor plus endocrine therapy compared with chemotherapy first line.

Initial Case Impressions and Treatment Options

This patient has now presented with some mildly symptomatic liver metastasis. She&rsquo;s got some fatigue and some intermittent nausea. The CT scan shows relatively smaller-volume liver metastasis, and it&rsquo;s likely that her liver function is still good to just mildly abnormal.

In older years we would have considered chemotherapy for this patient. But now we have very good evidence that CDK4/6 inhibitors work as quickly as chemotherapy with much less toxicitybut most important, the CDK4/6 inhibitors, the duration of response in the median progression-free survival, are far superior to chemotherapy. In fact, we are seeing a sea change away from chemotherapy in the first-line metastatic setting to CDK4/6 inhibitors, with the exception being someone who is in absolutely frank visceral crisis, in which case we would still utilize combination chemotherapy for that patient. Otherwise, we really should be looking at a CDK4/6 inhibitor with endocrine therapy for virtually everybody with first-line metastatic breast cancer.

There are 3 CDK4/6 inhibitors, all of which have been evaluated extensively in first-line and second-line metastatic breast cancer in combination with an aromatase inhibitor, first line, or with fulvestrant second line. This patient&rsquo;s disease has recurred on an aromatase inhibitor. So certainly we would be looking for fulvestrant with a CDK4/6 inhibitor. All 3 of the CKD4/6 inhibitorspalbociclib, ribociclib, and abemaciclib&mdash;have been studied extensively with fulvestrant in patients whose breast cancer has recurred on an aromatase inhibitor or within a year of finishing their adjuvant aromatase inhibitor therapy, or whose disease has recurred on adjuvant aromatase inhibitor therapy. So certainly I&rsquo;d be comfortable with any of the CDK4/6 inhibitors. The data all look excellent, with all 3 of them yielding very similar reductions in the risk of progression from their breast cancer.

We recently received important data at the American Society of Clinical Oncology [ASCO] 2018 Annual Meeting on the MONALESSA-3 clinical trial. There were 2 groups of patients who were all postmenopausal women, and they had either progression of their disease or recurrence of their disease on an aromatase inhibitor. They received fulvestrant with or without ribociclib, or they were first-line metastatic and had no prior endocrine therapy for metastatic disease and were beyond 1 year following completion of their adjuvant endocrine therapy.

A more naive or sensitive population received an endocrine therapy and fulvestrant with or without ribociclib. That was kind of a unique population because all the other CDK4/6 inhibitor trials in the first-line setting utilize an aromatase inhibitor with or without a CDK4/6 inhibitor. Here are our first data in MONALESSA-3 with fulvestrant in the first line with ribociclib. Not surprisingly, the ribociclib very substantially improved progression-free survival, both in the first-line setting and in the second-line setting, putting all the data together in the overall treated population. The median progression-free survival went from about 12.8 months or so up to a little bit more than 20 monthsa large improvement in the median . These are very, very good data, which show the safety and efficacy of the ribociclib with the fulvestrant. This will be an excellent choice for this patient. The other 2 CDK4/6 inhibitors would also be excellent because they all look very similar with regard to their efficacy with fulvestrant.

We have had excellent data with the CDK4/6 inhibitors in general with fulvestrant. All 3 of the CDK4/6 inhibitors have very similar safety and efficacy data with fulvestrant in patients whose breast cancer has progressed under the aromatase inhibitor. What&rsquo;s interesting and unique about the MONALESSA-3 study is it gave us unique data for first-line fulvestrant in combination with ribociclib; it looked quite excellent.

The other studies that have looked at fulvestrant in combination with a CDK4/6 inhibitor are PALOMA 3 with palbociclib, and the MONARCH 2 with abemaciclib. Just like the MONALESSA-3 in your aromatase inhibitor pretreated population, the addition of the CDK4/6 inhibitor to fulvestrant, regardless of the CDK4/6 inhibitor, really looked excellent. We&rsquo;re seeing unanimity of the effectiveness across the board with the CDK4/6 inhibitors.

Treatment Factors & Trial Data to Support Emerging Therapies

This patient has had 5 years of anastrozole, and unfortunately she has developed metastatic disease in her liver in spite of taking her anastrozole. Certainly we want to move away from the aromatase inhibitor family. We wouldn&rsquo;t want to continue the aromatase inhibitor, or change to a different one, and then add a CDK4/6 inhibitor, because we now have vast data for exactly this patient population. If a woman&rsquo;s disease is progressing or recurring on the aromatase inhibitor, or she switches to fulvestrant with a CDK4/6 inhibitor, she will really get substantial benefit.

The FALCON data were very important data, and I really like the trial because it was a head-to-head comparison of fulvestrant versus anastrozole in a completely hormonal-therapy-naive population, a very pure comparison of what is our most effective endocrine therapy; and the answer is fulvestrant. In the overall treated population, the fulvestrant had a superior progression-free survival [PFS] than anastrozole; however, that is a very specific patient population of completely endocrine-therapy-naive population.

Our patient here has been pretreated with anastrozole, and her breast cancer has recurred in spite of the anastrozole, so she doesn&rsquo;t fit the FALCON study population, which is fulvestrant by itself. Truthfully, now that we have the great data with the CDK4/6 inhibitors, we won&rsquo;t be using fulvestrant very often in the first-line setting by itself. There may be the occasional patient with small volume, asymptomatic metastatic breast cancer that&rsquo;s estrogen receptor [ER]&shy;positive and endocrine therapy sensitive; not a patient who is endocrine therapy sensitive and endocrine therapy naive, who lives a great distance from the cancer center or who has other substantial comorbidities, for which it wouldn&rsquo;t be in the patient&rsquo;s best interest to get a CDK4/6 inhibitor. This patient may be an appropriate candidate for fulvestrant alone; however, that&rsquo;s a very rare patient population, and I think the advantage of the FALCON trial is that it showed us the power of fulvestrant, and that&rsquo;s why the MONALESSA-3 data are very interesting because it brings the fulvestrant into the first line with ribociclib and shows excellent efficacy, giving physicians the opportunity to utilize fulvestrant in the first line with ribociclib if they so choose.

It&rsquo;s very likely that this woman is going to go on to treatment with fulvestrant and one of the CDK4/6 inhibitors. Truthfully, it&rsquo;s very likely that she&rsquo;s going to benefit from that because the CDK4/6 inhibitors have had a 70% to 80% chance of being beneficial with regard to either a response or clinical benefit in the metastatic population who have never had a CDK4/6 inhibitor before. Unfortunately, it&rsquo;s very likely that eventually she will have progression of disease on the CDK4/6 inhibitor with fulvestrant.

Today we have little data about what to do for that patient afterward, from the point of view of randomized clinical trials. We just had very important data come out at the European Society of Medical Oncology [ESMO] 2018 Annual Meeting, with regard to the SOLAR-1 trial, that&rsquo;s going to change practice because it showed that in the 35% to 40% of ER-positive, HER2-negative metastatic breast cancer patients, there will be a PIK3CA [phosphati-dylinositol-3 kinase, catalytic subunit, alpha isoform] somatic mutation in the breast cancer. Those patients will get substantial benefit with regard to PFS having alpelisib, the oral inhibitor of the PI3K kinase added to endocrine therapy. In the SOLAR-1 trial it was fulvestrant.

One option for this patient if she&rsquo;s found to have a

mutation is to potentially continue on the fulvestrant and have the alpelisib added. It was only 6% of patients in the SOLAR-1 trial that had had a prior CDK4/6 inhibitor. They benefited equally from the alpelisib compared with patients who had not had a prior CDK4/6 inhibitor. But the number of patients was indeed very small.

mutation in this patient, no question about it. I would also be comfortable if she had a slow progression after the CDK4/6 inhibitor and was asymptomatic. I would be very comfortable with a trial of everolimus for her with exemestane. If she had rapid progression in her liver, combined with other sites of metastases progressing as well, I would then probably favor capecitabine for her.

The important new information here is from the SOLAR-1 with the

-mutant population, which is 35% to 40% of patients like this, ER-positive, HER2-negative, having a

mutation. It&rsquo;s going to be important that we look for those mutations and consider alpelisib for that patient.

Trial-Supported Endocrine & Progression Therapy Shift

There has been great progress in estrogen receptor [ER&shy;]-positive, HER2-negative metastatic breast cancer recently. The CDK4/6 inhibitors are really a very important new therapeutic opportunity for patients because in the first-line setting, we&rsquo;re having median progression-free survivals of over 2 years. Now we have the introduction of our first PI3K inhibitor in this population, albeit just for the 35% to 40% of women whose breast cancers have a somatic mutation in PI3K.

I am really looking forward to triplet trials in the first-line setting with endocrine therapy and aromatase inhibitor or fulvestrant with a CDK4/6 inhibitor combined with either alpelisib or everolimus. I think we really want to block the PI3 kinase pathway and the CDK4/6 with excellent inhibition of the estrogen receptor to really get dramatic and even more prolonged progression-free survival [PFS] for patients. There are these triplet studies ongoing right now, and I really look forward to those data in the future to see if we can truly make breast cancer into a chronic disease with extremely long progression-free survival in the first-line setting.

Recurrent HR+ Breast Cancer

Initial Case Impressions and Treatment Options

Treatment Factors & Trial Data to Support Emerging Therapies

Trial-Supported Endocrine & Progression Therapy Shift

Case Summary and Optimisms for Future Advancements