Episode 056: Breast Cancer Series, Pt. 5-Breast Cancer Pharmacology
So much incredible progress has been made in the management and treatment of breast cancer, largely thanks to advances in available therapies and drugs. A good understanding of pharmacology is key to selecting the correct regimen and providing counseling to your patients. This week, are so fortunate to be joined by special guest Dr. Danielle Roman, PharmD, who is an Oncology Clinical Pharmacy Specialist at West Penn Allegheny Oncology Network in Pennsylvania, as she helps us navigate breast cancer pharmacology.
This episode has been sponsored by HemOnc.org.
Endocrine therapy
How to define menopause when deciding about endocrine therapy?
When considering patients for endocrine therapy, we think of patients as one of either postmenopausal or premenopausal categories:
Women >60 are considered postmenopausal
For women <60, menopause is defined by amenorrhea for >12 months as well as FSH and estradiol in the post menopausal range.
How GnRH agonist (Leuprolide, goserelin) causes ovarian suppression and what is the frequency of dosing?
GnRH agonists include: Leuprolide (Lupron) and Goserelin (Zoladex)
Mechanism of action:
Initially (1-2 weeks) cause a surge of FSH and LH, which stimulate ovaries to release estradiol.
Ultimately causes negative negative feedback which inhibits ovarian estrogen production.
Differences between Leuprolide and goserelin:
Lupron- IM every 28 days (3.75 mg) or 3 month depot formulation (11.25mg).
NOTE: Lower dosing is used in breast cancer as compared to prostate cancer!
Goserelin- SubQ (small pallet-like implant in the abdomen) every 28 day dosing.
How to counsel patients on the side effects of Tamoxifen?
Tamoxifen is a Selective estrogen receptor modulator: antagonist in breast, agonist in uterus and bone
Side effects include: Irregular menses, night sweats, hyperlipidemia, menopausal symptoms (more severe than in natural menopausal state): hot flashes, vaginal dryness.
Bone loss (in premenopausal). Has protective effect on postmenopausal.
Rare side effects: VTE, risk of uterine cancer (in post-menopausal patients).
Patients should be counseled about avoiding prolonged immobility, and to look out for abnormal uterine bleeding.
Patients should have regular gynecological follow up.
How to manage Vasomotor symptoms?
Make sure patients avoid herbal supplements as the majority contain phytoestrogens!! (plant-based estrogens)
Pharmacological treatments:
1st line: Venlafaxine, citalopram, escitalopram, sertraline
Gabapentin for hot flashes
Clonidine can also be used.
Non-pharmacologic treatments:
Acupuncture, yoga, exercise.
What are the major drug interactions of Tamoxifen?
CYP2D6 converts tamoxifen into active metabolite endoxifen.
Fluoxetine, paroxetine and bupropion are strong inhibitors of CYP2D6 and should be avoided with Tamoxifen.
Citalopram, escitalopram, venlafaxine, sertraline have minimal impact on CYP2D6 and can be safely used with Tamoxifen.
What are the differences in the side effect profiles of Letrozole (Aromatase Inhibitors) vs SERMs?
Menopausal symptoms are the same!
DVT and uterine cancer are not a concern with AI
With AI, bone loss in postmenopausal is a concern and should be monitored with baseline DEXA scan and every 2 years afterwards.
AI class also causes arthralgias and myalgias: occur in 50% of patients.
Usually begin after 6 weeks of treatment, can worsen during the first year of treatment and can be very debilitating for some patients.
Patients with baseline joint problems are particularly at risk.
Management: Duoloxetine, Acupuncture, Exercise.
Switching to an alternate AI can sometimes be helpful.
ER+ disease
How to reduce alopecia associated with Taxanes and Cyclophosphamide (TC) x 4 (TAILORx trial)? What is scalp cooling?
TAILORx trial: Showed improvement in survival by some points with TC as adjuvant Chemotherapy in hormone positive breast cancer.
q21 day cycle of Docetaxel and Cyclophosphamide as adjuvant therapy in hormone positive breast cancer
Usually no patients are able to keep their hair with TC, with alopecia being the side effect of both Cyclophosphamide and Taxanes.
2 weeks into 1st cycle is when there is bulk of hair loss.
Total body alopecia occurs with taxanes, including eyebrow and eyelashes.
Usually reversible.
Scalp cooling is a technique used to reduce alopecia. Cooling cap is worn for sometime before the treatment and kept throughout the treatment and for sometime (1-3 hrs) afterwards.
Limited data is available to support efficacy.
Mechanism: Vasoconstriction with less chemo exposure to the hair follicles.
When is dose reduction considered for taxanes?
When Neuropathy is limiting ADLs.
20% dose reduction in grade 2-3 neuropathy
Neuropathy is completely reversible.
What is “Dose dense” Neo adjuvant AC-T (ddAC-T)?
Doxorubicin, cyclophosphamide is given in a “dose dense”manner.
Doses are the same but there is shorter interval (2 weeks) between doses compared to the standard every 3 weeks regimen.
Neutropenia occurs with dose dense therapy.
Patients need to be given prophylactic growth factors upfront because they are not getting enough time for recovery.
Nausea is not different with dose dense therapy compared to traditional dosing.
Regardless, AC causes severe nausea and should be treated aggressively.
Goal should be to prevent it: Prophylactically, 4 drug regimen can be given including Steroids (dex), 5HT3 antagonist (Ondensetron) , NK-1 antagonist (aprepitant, fosaprepitant),Olanzapine.
Nausea, vomiting can linger for days to weeks after treatment. Delayed Dexa (8mg) for 3 days after treatment is very helpful.
Triple negative disease
What is KEYNOTE-522 trial and how often do these patients need to come to infusion center?
KEYNOTE- 522 trial: (TC-AC (Carboplatin, Paclitaxel +Pembrolizumab) x 12 weeks followed by (Doxorubicin+Cyclophosphamide+Pembrolizumab) x 12 weeks to complete neoadjuvant therapy.
The trial looks at 2 different ways of giving Carboplatin:
Every 3 week carboplatin vs weekly Carboplatin.
Weekly Carboplatin was found to be better tolerated.
There are 2 phases of treatment:
1st phase: Weekly Carboplatin for 12 weeks
2nd phase: AC treatment every 3 weeks ( but patients are seen more frequently than this in Danielle’s practice to check labs and make sure patients are hydrated as it is a very intense regimen).
HER2+ disease
What are the side effects of TCHP Neo adjuvant therapy with in HER-2 +ve breast cancer?
These patients get Docetaxel, Carboplatin + combination of 2 HER-2 Neu directed therapies (Trastuzumab (Herceptin) + Pertuzumab (Perjeta)).
S/E of Trastuzumab and Pertuzumab:
Cardiotoxic:
Trastuzumab is most cardiotoxic
Get echocardiogram at baseline and every 3 months.
Infusion related reactions: usually not very common or severe.
Diarrhea: More with pertuzumab.
In case of severe diarrhea, pertuzumab can be dropped.
Other important agents
What is the mechanism of action of antibody drug conjugates such as Trastuzumb Emtansine (also known as TDM1 or Kadcyla)?
They have 3 components: An antibody, a linker and a cytotoxic component.
This way, cytotoxic drug is delivered in a targeted way.
Antibody targets the Her-2 receptor and the cytotoxic component, which is Emtansine is delivered to the cell which inhibits microtubule assembly.
Another example of antibody drug conjugate is Trastuzumab-Deruxtecan (Topoisomerase inhibitor).
What is the mechanism of action of CDK4/6 inhibitors?
3 agents: Palbociclib, Ribociclib, Abemaciclib.
CDK4/6 binds to Cyclin D1 which causes activation of retinoblastoma (Rb) protein which ultimately causes cell cycle progression. By inhibiting CDK46, these drugs block cell cycle at G0-G1 phase.
What are the side effects of CDK4/6 inhibitors?
Palbocilib causes neutropenia
Ribociclib causes QT prolongation
Abemaciclib causes Diarrhea (>75% patients develop diarrhea, usually within 1st week of treatment).
Usually low grade and manageable with loperamide, encouraging PO hydration and dietary changes.
Grade 2 diarrhea: 4-6 stools over baseline warrants dose reduction.
Diarrhea tends to improve/subside over time.
When is fulvestrant used in breast cancer and how is it administered?
Fulvestrant has similar mechanism of action to tamoxifen.
Selective for estrogen receptors but does not just binds but degrades the receptors.
It is used in post-menopausal women in metastatic setting.
Using in pre-menopausal women requires a GnRH agonist on board.
Can be used as front line or later in treatment.
Administration: IM Gluteal injection.
2 injections to get the total dose- 1 in each buttock.
It is viscous, pushed slowly and painful for the patient
Loading dose: every 2 weeks for a total of 3 times
After loading dose, monthly injections.
What is the role of swish therapy for everolimus induced stomatitis (SWISH study)?
Dexamethasone solution (should be alcohol free- 0.5mg/5ml oral solution).
1mg or 10 ml swished for 2 minutes and then spit it out 4 times a day.
Avoid food/drink within 1 hour of treatment.
Grade 2 stomatitis: Moderate Pain.
Should definitely do dose reduction, consider temporary hold.
Grade 3: Difficulty with oral intake, severe pain:
Temporary hold, allow for some improvement and then dose reduction.
Elacestrant is a new SERM for patients with ESR-1 mutation which can be used in place of fulvestrant to avoid painful injections!
About our guest!
Dr. Danielle Roman, PharmD is an Oncology Clinical Pharmacy Specialist at West Penn Allegheny Oncology Network in Pennsylvania. She received her PharmD from Duquesne University after which she did her residency training at Johns Hopkins Hospital.
References:
TAILORx Trial: Adjuvant chemotherapy guided by a 21 Gene expression assay in breast cancer. DOI: 10.1056/NEJMoa1804710. Showed improvement in survival by some points with TC as adjuvant Chemotherapy in hormone positive breast cancer.
KEYNOTE-522 trial : Pembrolizumab for early triple negative breast cancer. DOI: 10.1056/NEJMoa1910549
SWISH trial: https://doi.org/10.1016/S1470-2045(17)30109-2
Prevention of everolimus-related stomatitis in women with hormone receptor positive, HER-2 negative metastatic breast cancer using Dexamethasone mouthwash.
This episode is sponsored by HemOnc.org!
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Maria Khan, Ronak Mistry
Social media management: Ronak Mistry
We are proud to partner with HemOnc.org!
Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org
This episode was created in collaboration with our friends at Pharmacy Podcast Network!
