Testing and Treatment Exposure Affect Options in Advanced Breast Cancer

Stephanie L. Graff, MD (Moderator)

Director of Breast Oncology

Lifespan Cancer Institute

Providence, RI

CASE SUMMARY

• A 52-year-old, postmenopausal fitness instructor presented with a palpable mass in the upper, outer quadrant of her right breast, without apparent axillary involvement.

Medical/Social History

• Two pregnancies and 2 deliveries after 24 weeks
• Menopause: age 48 years
• No chronic comorbidities
• No concomitant prescription medications
• Most recent, negative mammogram: age 42
• Never smoker

Initial Diagnostic and Surgical Procedures

• ECOG performance status: 0 ​
• Diagnostic mammogram: high density mass with irregular margins and segmental microcalcifications
• Breast ultrasound: opaque, irregular, 34-mm mass with spiculated margins visualized at 3 o’clock in the right breast
• Core biopsy: estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, HER2-negative ​grade 2 invasive ductal carcinoma (IDC); Ki-67 24%
• Lumpectomy and sentinel lymph node (SLN) biopsy: 38 mm, grade 2 IDC, no evidence of micrometastasis or isolated tumor cells from 2 SLNs on immunohistochemistry (IHC)
• RT-PCR 21-gene recurrence score: 27
• Staging: T2N0M0
• Adjuvant therapy:
  • Docetaxel/cyclophosphamide
  • Letrozole (Femara) for 5 years

Three Years After Completing Letrozole

• The patient presented with persistent low-back pain and fatigue, which restricts vigorous, prolonged exercise.

Follow-Up Diagnostic Tests

• ECOG performance status: 0 ​
• Complete blood count and differential: hemoglobin, 9.8 g/dL; all other indices within normal limits
• [18F] FDG PET/CT: avid radiotracer uptake detected in L4-L5 vertebrae and right pubic bone
• Biopsy of L4 bone lesion: malignant cytokeratin positive cells consistent with primary breast adenocarcinoma
• ER/PR-positive, HER2 IHC 0
• Restaging:T2N0M1b (metastatic)

First-Line Therapy: CDK4/6 inhibitor + aromatase inhibitor

• Patient had initial partial response, but after 16 months, showed evidence of disease progression new areas of bone involvement in T-spine, left ribs, and L2.
• Patient has wild type ESR, no actionable mutation in PIK3CA, PTEN, or AKT, and no germline BRCA mutation.
• Received fulvestrant (Faslodex) plus everolimus (Afinitor) for 6 months. ​
• Radiographic evidence of disease progression with numerous new bony metastases
• Treated with capecitabine, which she tolerated reasonably well with grade 1 hand-foot syndrome

After 9 Months of Chemotherapy

• CT chest/abdomen/pelvis and bone scan: 2 liver lesions, 1.8 cm and 2.4 cm;persistent bony metastases consistent with disease progression; small lung lesions too small to characterize but in setting of other findings concerning for metastatic disease

Follow-Up Diagnostic Tests

• ECOG performance status: 1
• Laboratory profile: within normal limits

Treatment

• Sacituzumab govitecan (Trodelvy) was initiated.
• Patient maintained an absolute neutrophil count of 3,900/μL and white blood cell count of 7,800/μL
• Initial grade 2 diarrhea quickly resolved with improved utilization of antidiarrheal medications.
• Follow-up CT scan of chest/abdomen/pelvis and bone scan demonstrated resolution of pulmonary lesions, and partial response in liver and bone metastases

DISCUSSION QUESTION

• Do you test for UGT1A1*28 prior to initiating sacituzumab govitecan?

STEPHANIE L. GRAFF, MD: Are any of you testing for UGT1A1*28 in your practices right now?

ROBERT HOROWITZ, MD: No, but we've talked about it.

MADHURI YALAMANCHILI, MD: I tested 1 patient after she had a lot of cytopenias, even after 1 dose, because her son requested it. She had heterozygous [genotype], which was surprising. I already gave her dose reductions because she had a hard time through adjuvant therapy, but she still had a hard time. But [I didn’t test] proactively, just at request by the family.

GRAFF: I feel like it should be an easy thing to do. Implementing institutional policies that are simple and easy to follow uniformly is never as easy as it should be. I hope [soon] I'll be able to tell you confidently that we're doing it and we have risk-benefits about this strategy of continuing [therapy] in our zygote carriers moving forward, so more to come.

PAUL S. UNGER, MD: Are there accepted dose reductions or dose differences that you would use based on the testing? Or is it more, if there is something, beware, because we've been around on this with the 5-FU dihydropyrimidine dehydrogenase testing in the past, and you can have an abnormal result in someone who tolerates it fine, and patients who don't tolerate it with a normal result. I understand the mechanism, [but if we] don't know enough about it. If we start testing patients, we might be dose reducing patients who may or may not have a problem.

GRAFF: I don't think that we have the right answer or the prospectively validated answer to your question. My anecdotal thoughts would be that if I found somebody who had it, and [sacituzumab govitecan] was their best treatment option, I would probably start them at a reduced dose. Alternatively, if I found someone who had it and I was trying to decide between numerous potential lines of therapy, it would steer me to make a different choice. One of the luxuries of being a breast oncologist is that we do often have a choice, and so it might be worth knowing. Time will tell.

DISCUSSION QUESTIONS

• What do you envision to be the role of antibody-drug conjugates (ADCs) in the treatment of hormone receptor–positive metastatic breast cancer?
  • How many lines of chemotherapy before you consider—and how does adjuvant therapy/timing of adjuvant therapy impact your thinking?

GRAFF: How are you thinking about lines of chemotherapy? In this patient case, her chemotherapy had been 8 years prior, and that was her docetaxel exposure. How does that timing affect when you're using sacituzumab vs reusing a taxane or a different ADC?

TARA BERMAN, MD, MS: I treat mostly gynecologic malignancies, so for us, our rule of thumb is recurrence 6 months later, then we'll call them platinum sensitive so then we can reintroduce. I don't know if you do the same thing with paclitaxel. I just started treating breast malignancies so I'm here to hear what the consensus is among everyone else, but I am just trying to extrapolate my knowledge from gynecologic oncology.

GRAFF: That's probably accurate for triple-negative breast cancer because the proliferative rate and the cellular biology of the cancer is so much more similar to ovarian cancer in the biologically aggressiveness of the tumor. In hormone-receptor positive disease, I just don't know if that's true. I counted the taxane for this case because I had used docetaxel up front. But single-agent paclitaxel is well tolerated and sometimes it's hard, especially in older patients in whom I’m worried about the adverse event profile, not to use that earlier than some of the ADCs, so it's always a good discussion.