Oral SERDs Provide a Stronger Option in ESR1+ Advanced Breast Cancer

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In the first article of a 2-part series, Komal Jhaveri, MD, guides a conversation on treatment options for patients with ESR1-positive metastatic breast cancer.

Komal Jhaveri, MD

Section Head, Endocrine Therapy Research Program

Clinical Director, Early Drug Development Service

Patricia and James Cayne Chair for Junior Faculty

Memorial Sloan Kettering Cancer Center​

New York, NY

Komal Jhaveri, MD

Section Head, Endocrine Therapy Research Program

Clinical Director, Early Drug Development Service

Patricia and James Cayne Chair for Junior Faculty

Memorial Sloan Kettering Cancer Center​

New York, NY

CASE SUMMARY

A 56-year-old, postmenopausal woman presents with a palpable right breast mass with no clinically abnormal axillary lymph nodes. Core biopsy showed the patient had grade II invasive ductal carcinoma (IDC), was estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+) and had HER2 immunohistochemistry (IHC) of 0; Ki-67 was at 33%. Lumpectomy and sentinel lymph node (SLN) biopsy showed a 3.0 c grade 2 IDC, but 2 SLNs were negative for malignant cells. The patient had a 21-gene recurrence score of 27 then received docetaxel and cyclophosphamide for 4 cycles followed by radiation therapy and completed 5 years of adjuvant aromatase inhibitor (AI).

Three years later after completion, she reported right-sided abdominal pain and mild nausea. A CT scan showed 3 suspicious liver lesions (right lobe, largest 2 cm) and a liver biopsy showed adenocarcinoma consistent with breast primary ER+/PR+, HER2 IHC 0. Her liver enzymes were normal and comprehensive molecular testing from the tissue biopsy showed no actionable alterations. AI plus palbociclib (Ibrance) was initiated. The therapy was tolerated well, with grade 2 neutropenia that did not require dose modification of palbociclib. Twenty months later, follow-up imaging showed increased size of both liver nodules and 2 new lung nodules, the largest measuring 0.9 cm. Her ECOG performance status is now 0, and liver enzymes are still normal.

DISCUSSION QUESTIONS:

  • Have you used the oral selective estrogen receptor degrader (SERD) elacestrant (Orserdu) for your patients with breast cancer?​
  • Do you have experience with any other investigational oral SERD or endocrine therapy? ​
  • What efficacy and/or safety data most impacts your decision to prescribe oral SERDs, approved or investigational?

DAYA S. SHARMA, MD: I've had 1 patient who's been on elacestrant for the last 6 months without any [toxicity issues] and the patient has still done well. The patient also has a PIC3K mutation.

KOMAL JHAVERI, MD: That's in line with what we saw with [the EMERALD study (NCT03778931)], which showed elacestrant was well tolerated with very low-grade nausea and nothing else [of note] otherwise.1

KAVITA B. KALRA, MD: I've had 1 patient where we've been actively talking about using it, but she had the PI3K mutation as well as the ESR1 mutation. The daughter of that patient is an internist, so we figured that we could try and get her through the PI3K inhibitor array, but it's a very tough treatment. I think even with all the support and having a physician who knows how to deal with diabetes on a daily basis, it was very difficult. It was mostly the gastroparesis, and I think overall the gastrointestinal toxicity prevented that PI3K inhibitor from working well. We're in that phase now where she might be starting elacestrant soon, but nobody is currently on the drug.

ARUN BHANDARI, MD: Are there efficacy data with fulvestrant [in patients with a] ESR1 mutation in their disease?

JHAVERI: We know that some of these other mutations may have activity with fulvestrant, which is why the trial of fulvestrant [NCT00075764] did show benefit, but in certain alterations we don't [see it].2 What we also saw from the EMERLAD trial is that despite fulvestrant and ESR1 mutation activity, the progression-free survival is about 2 months, so it's barely anything [with fulvestrant] and it's not optimal.1

QAMAR U. ZAMAN, MD: I had a patient who progressed [on elacestrant] after 3 months, but she tolerated it well. I have a question: With the use of metformin [in patients on a PI3K inhibitor], are they better tolerated? Or did it not improve the hyperglycemia because there are so many other adverse events [AEs]?

JHAVERI: Hyperglycemia is the most common AE. There was a retrospective analysis of a single institutional data [from the SOLAR-1 trial (NCT02437318)] set to look at hemoglobin A1C, and what we found was for those patients who had a baseline hemoglobin A1C of more than 6.4 g/dl did badly with the hyperglycemia AE.3 But those who had closer to 5.7 g/dl—so a normal glycemic sore, not too bad BMIs, and not too bad hemoglobin A1C—potentially tolerated metformin better, but I think you have to remind the patient of the lifestyle and dietary modifications and very strict glucose control. The Spanish group studied prophylactic metformin in the METALLICA trial [NCT04300790], where they gave a ramp up of 2 weeks of metformin before the patient started alpelisib [Piqray], and they showed with that approach that the grade 3 toxicity rates were low in the order of 67% compared with 36% that was reported out initially.4

I don't necessarily start them on day 1 or ramp them up, but I do look at the hemoglobin A1C and I do start talking about the diet that I want my patients to do. If there's a patient who's slightly overweight or has a slightly higher hemoglobin A1C level, I will have them check their fingerstick blood glucose as soon as they start their alpelisib and have a very low threshold for starting metformin as soon as that glucose starts becoming grade 2. That's how I monitored them, but I would not be opposed to metformin for somebody who might be at higher risk.

References:

1. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338

2. Mehta RS, Barlow W, Albain K, et al. Overall survival with fulvestrant plus anastrozole in metastatic breast cancer. N Engl J Med. 2019; 380:1226-1234. doi:10.1056/NEJMoa1811714

3. Burnette SE, Poehlein E, Lee HJ, et al. Evaluation of alpelisib-induced hyperglycemia prophylaxis and associated risk factors in PIK3CA-mutated hormone-receptor positive, human epidermal growth factor-2 negative advanced breast cancer. Breast Cancer Res Treat. 2023;197(2):369-376. doi:10.1007/s10549-022-06798-8

4. Borrego M, Tolosa P, Blanch S, et al. Abstract PD8-02: Metformin (MET) for the prevention of alpelisib (ALP)-related hyperglycemia (HG) in PIK3CA-mutated, hormone receptor-positive (HR[+]) HER2-negative (HER2[-]) advanced breast cancer (ABC): The METALLICA study. Cancer Res. 2023;83(5):PD8-02. doi:10.1158/1538-7445.SABCS22-PD8-02

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