Case Study 11

For each question, choose the answer you think is correct. Answers are provided at the end of the page.
​​​​​​​A.P. is a 50-year-old female diagnosed with metastatic breast cancer with a primary lesion in the left breast and disease involving bones, lungs and liver. Tumour is ER-positive, PR-positive, and HER2-negative. She has pain in her right upper quadrant radiating tow​ards the left scapula which is sometimes severe. She is also on zoledronic acid. She will be starting treatment with BRAVRBFLV​.

Lab results taken 24 hours prior to first treatment:

Lab value
 Patient's labs
 Normal range 
WBC
3.3
4 – 10 x 109/L
ANC
1.7
2 – 7.5 x 109/L
Hgb
142
115 – 155 g/L
Plt
190
150 – 400 x 109/L
SCr
54
45 – 90 µmol/L
eGFR
93
≥ 60 mL/min/1.73m2
​Sodium
​139
​135 - 145 mmol/L
​Potassium
​4.1
​3.5 - 5 mmol/L
​Albumin
​38
​35 - 50 g/L
​Calcium
​2.23
​2.10 - 2.60 mmol/L
​Magnesium
​0.78
​0.64 - 0.98 mmol/L
GGT
34
<49 U/L
AST
26
<36 U/L
ALT
32
<36 U/L
ALP
128
35 – 120 U/L
Total bilirubin
7
<17 µmol/L
LD
156
<225 U/L

Weight = 53.8 kg, Height = 160 cm, QTc = 423 ms

1.  Which of the following patient populations would be eligible to receive ribociclib?  

  1. Post-menopausal women with ER-negative, HER-2 positive advanced breast cancer with no prior systemic treatment for metastatic disease
  2. Women receiving concurrent ovarian suppression with no prior fulvestrant treatment for metastatic disease
  3. Post-menopausal women with ER-positive, HER-2 positive advanced breast cancer with prior systemic chemotherapy for metastatic disease
  4. Post-menopausal women with ER-positive, HER-2 negative advanced breast cancer with no prior systemic treatment for metastatic disease
  5. Options 1 and 2 are correct
  6. Options 2 and 4 are correct

2. What is the standard dosing regimen of ribociclib? 

  1. 600 mg PO once daily continuously until disease progression or unacceptable toxicity
  2. 600 mg PO once daily for 3 weeks, then 1 week off until disease progression, unacceptable toxicity, or a maximum of 2 years of treatment
  3. 600 mg PO once daily in the morning for 3 weeks, then 1 week off until disease progression or unacceptable toxicity
  4. One injection given subcutaneously every 3 months until disease progression or unacceptable toxicity
  5. 600 mg PO once daily in the evening for 3 weeks, then 1 week off until disease progression or unacceptable toxicity
  6. Options 3 and 5 are correct

On Day 15 of Cycle 1, A.P's bloodwork reveals the following: ANC = 0.8 (x 109/L), Platelets = 100 (x 109/L). Per protocol, she continues treatment at the same dose.

3. Hematology is repeated on Cycle 1 Day 22: ANC = 0.7 (x 109/L), Platelets = 105 (x 109/L).  Per protocol, which of the following would be the most appropriate Cycle 2 treatment plan?

  1. Not applicable, there are no dose modifications based on Cycle 1 Day 22 bloodwork
  2. Delay the start of Cycle 2 by 1 week; provided ANC recovers to ≥ 1 (x 109/L), resume treatment at the same dose
  3. Delay the start of Cycle 2 by 1 week; provided ANC recovers to ≥ 1 (x 109/L), resume treatment at the next lower dose
  4. Keep treatment as scheduled (without delay); provided ANC recovers to ≥ 1 (x 109/L) prior to Cycle 2, continue treatment at the same dose
  5. Keep treatment as scheduled (without delay); provided ANC recovers ≥ 1 (x 109/L) prior to Cycle 2, continue treatment at the next lower dose

4.  A.P. returned to clinic in anticipation of Cycle 2 with Day 1 blood work reporting: ANC = 0.4 (x 109/L), Platelets = 100 (x 109/L). Her ribociclib treatment was delayed for 1 week. What should happen to the timing of her fulvestrant injection?

  1. ​Fulvestrant should also be delayed 1 week to align with ribociclib timing
  2. Fulvestrant should be given today as originally scheduled, and again on day 15
  3. Fulvestrant should be given today as originally scheduled, and repeated every 28 days regardless of ribociclib timing
  4. Fulvestrant should be omitted for cycle 2 as it may be contributing to her neutropenia

​5. Repeat bloodwork one week later reports: ANC = 1.1 (x 109/L), Platelets = 153 (x 109/L). Per protocol, which of the following would be the most appropriate treatment plan?

  1. Resume treatment at the same dose as previous, 600 mg/day
  2. Resume treatment at the next lower dose, 400 mg/day
  3. Delay treatment for 1 more week, then resume at the same dose as previous, 600 mg/day
  4. Resume treatment at the next lower dose of 200 mg/day 

A.P.’s ECG prior to Cycle 2 shows a QTc interval of 457 ms and she is asymptomatic. You determine that this QTc change is within acceptable limits per the BRAVRBFLV protocol. 

6. How would you proceed if A.P.’s QTc interval had been 485 ms and she was experiencing symptoms of syncope and arrythmia?

  1. Permanently discontinue ribociclib
  2. Delay ribociclib. If QTc resolves to less than 481 ms, restart at the same dose level
  3. Delay ribociclib. If QTc resolves to less than 481 ms, restart at the next lower dose
  4. Continue ribociclib as scheduled, 485 ms is within 5% of the 480 ms cut off

​7. Which of the following would best explain why A.P. is also receiving zoledronic acid (protocol BRAVZOL)?

  1. She has symptomatic hypocalcemia
  2. She has a history of atypical femoral fracture
  3. She is experiencing acute bone pain
  4. She has a diagnosis of osteopenia 

8. A.P. now returns to clinic in anticipation of Cycle 8, but without any bloodwork. Based on the protocol, would it be okay for her to proceed with treatment today without current labs?

  1. Yes, after Cycle 7, bloodwork monitoring is no longer required
  2. Yes, results from Cycle 7 are available and bloodwork should be repeated prior to Cycle 10
  3. No, bloodwork should be monitored with each subsequent cycle 
  4. Yes, results from Cycle 7 are available and bloodwork should be repeated prior to ​Cycle 9

Answer 1
​The correct answer is 6.

Rationale: As per the revised eligibility of BRAVRBFLV, men and pre-menopausal women who are on concurrent ovarian suppression (with LHRH agonists) are also eligible to receive treatment in addition to post-menopausal females. 

Patients with HER-2 positive disease, those who have received more than one prior line of chemotherapy for advanced or metastatic disease, patients resistant to prior adjuvant abemaciclib therapy, and those who have received everolimus are not eligible to receive BRAVRBFLV treatment. For patients recently diagnosed with metastatic breast cancer who initiated fulvestrant monotherapy within the past 6 months, ribociclib can be added if the remaining eligibility criteria are met.

Answer 2
​The correct answer is 3.

Rationale: According to the BRAVRBFLV protocol, ribociclib is taken at a starting dose of 600 mg orally once daily for 21 days on, 7 days off with one cycle being 28 days long, until disease progression or unacceptable toxicity.

As per the Precautions section of the BRAVRBFLV protocol, ribociclib is to be taken in the morning as QT prolongation risk may be increased when it is taken in the evening due to bradycardia which naturally occurs during sleep.

Answer 3
The correct answer is 4.

Rationale: Based on the BRAVRBFLV Dose Modifications table, if ANC is between 0.5 to less than 1 (x 109/L) on Days 15 and 22, treatment can be continued at the same dose level.

Answer 4
​The correct answer is 3.

Rationale: According to the Treatment section of the BRAVRBFLV protocol, if ribociclib is delayed/held/omitted, fulvestrant treatment should be continued as planned. Fulvestrant is administered on Day 1 and Day 15 of Cycle 1 only, then on Day 1 of Cycle 2, then repeated every 28 days for the duration of treatment. Fulvestrant does not cause neutropenia, as per the Side Effects table of the Cancer Drug Manual fulvestrant monograph.

Answer 5
The correct answer is 2.

Rationale: Based on the BRAVRBFLV dose modification table, if the patient experiences grade 4 neutropenia (ANC < 0.5 (x 109/L), hold treatment until ANC ≥ 1 (x 109/L), and resume treatment at next lower dose.

Answer 6
​​The correct answer is 1.

​Rationale: If A.P.’s QTc interval rises from 423 ms at baseline to 485 ms pre-Cycle 2, this represents an absolute increase of 62 ms. Based on subsection 4., QT interval prolongation, of the Dose Modifications section in the BRAVRBFLV protocol, if QTc interval prolongation is either greater than 500 ms or greater than 60 ms from baseline AND associated with torsades de pointes or polymorphic ventricular tachycardia, unexplained syncope or signs/symptoms if serious arrhythmia, ribociclib should be permanently discontinued.

Answer 7
​The correct answer is 3.

Rationale: The BRAVZOL protocol indicates that breast cancer patients with metastasis to bone are eligible for treatment if they experience an acute pain crisis or to decrease skeletal related events. Hypocalcemia and atypical femoral fracture are potential adverse reactions of bisphosphonate therapy.

Answer 8
​The correct answer is 4.

Rationale: As per the tests section of the protocol, bloodwork monitoring requirements for Cycle 7 onwards are based on ANC values from Cycles 1-6, with the ANC threshold being 1 (x109/L). During the first 6 cycles of treatment, A.P.’s ANC dropped below 1 (x109/L), and therefore, per protocol, bloodwork should continue to be monitored every one to two cycles of treatment.
​​​​​​​​​​​​​​​​​​​​​

The correct answer is 3.

Rationale: As per the tests section of the protocol, CBC monitoring requirements for Cycle 7 onwards are based on ANC values from Cycles 1-6, with the ANC threshold being 1 x109/L.  During the first 6 cycles of treatment, A.P.'s ANC dropped below 1 x109/L, and therefore, per protocol, CBC should continue to be monitored with each cycle of treatment.