Management of BreastCancer Treatment Related

Complications/ParticularitiesRegarding Follow-up

Pierre Whitlock M.D.,F.R.C.P.C

Hematologist & Medical Oncologist

Dr Leon Richard Oncology Center

Moncton NB

Disclosures

• Adboards and Speaker for Pharmaceutical Companies

Introduction

• Breast Cancer is the most frequently diagnosed cancer in women

• Leading cause of death from cancer in women worldwide

• 75% are ER(+) +/- PR(+)

• 20% are Her-2-Neu

• 20% are called triple (-); ER(-) + PR(-) + Her-2-Neu (-) = more commonly in women younger than 40 yo

Introduction: Background /Epidemiology

• In Canada for 2017: 206,300 new cases of cancer

• Females: 103,200 new cases

• 25.5% were Breast Cancer= 26,300

• 5000 deaths related to Breast Cancer in 2017

• On average, 72 Canadian women will be diagnosed with breast cancer every day

• On average, 14 Canadian women will die from breast cancer every day

Breast Cancer - Background and Epidemiology

~ 26,300 expected new cases of breast cancer (BC) in Canada for 2017 or ~25% of all new female cancer cases.

On average, 72 Canadian women will be diagnosed with breast cancer every day.

On average, 14 Canadian women will die from breast cancer every day.

5,000 deaths expected in Canada for 2017

Source: Canadian Cancer Statistics 2017; http://www.cancer.ca/~/media/cancer.ca/CW/cancer%20information/cancer%20101/C

anadian%20cancer%20statistics/Canadian-Cancer-Statistics-2017-EN.pdf?la=en

Introduction: Breast Cancer stages and associated survival

• Stage 0 100 % 5-year relative survival

• Stage 1 over 90%

• Stage 2 80%

• Stage 3 70%

• Stage 4 22%

Introduction:Breast Cancer stages and associated survival

• POPULATION-BASED SCREENING AND ADVANCES IN ADJUVANT THERAPY HAVE CONTRIBUTED TO DECLINING BC DEATH RATES OVER THE LAST FEW DECADES.

• Metastatic breast cancer still remains an incurable disease associated with a 24-month median overall survival

Introduction: Early-Stage Breast Cancer

• Adjuvant therapy: reduce risk of recurrence after surgery

• Neoadjuvant therapy: reduce tumor size prior to surgery + reduce risk of recurrence

• GOAL: CURATIVE TREATMENT

Introduction: Advanced/Metastatic BreastCancer

• 5-10 % at BC diagnosis

• Palliative Therapy: Prolong survival and control disease symptoms

• GOAL: SLOW PROGRESSION AND MAINTAIN QOL

Introduction

• 3 differents options of systemic therapy in post-operative or adjuvant

• Hormonal manipulation=hormonotherapy

• Cytotoxic treatment=chemotherapy

• Targeted-therapy (vs the H-2-N antigen)= trastuzumab (Herceptin)

Treatment Approvals for HR+ Metastatic Disease Have Been Ongoing, Much Has Been Learned, and Multiple Drugs Targeting New Pathways Are Under Development

*Various chemotherapy agents have been approved(capecitabine, eribulin mesylate, paclitaxel),but do not target HR+ disease specifically10–12

CDK, cyclin-dependent kinase; ER, estrogen receptor; HR,hormone receptor; MBC, metastatic breast cancer;mTOR, mammalian target of rapamycin;PI3K, phosphoinositide 3-kinase

1. Jordan VC. Steroids. 2007;72(13):829-842. 2. Health Canada NOC database. 3. http://webprod5.hc-sc.gc.ca/noc-ac/search-recherche.do?lang=eng ; 4. Milani A, et al. World J Clin Oncol. 2014;5:990-1001; 5. Osborne CK, et al. Annu Rev Med. 2011;62:233-247; 6. Lange CA, et al. Endocr Relat Cancer. 2011;18:C19-

C24; 7. Asghar U, et al. Nat Rev Drug Discov. 2015;14:130-146; 8. Baselga J. Oncologist. 2011;16(suppl 1):12-19; 9. Vicier C, et al. Breast Cancer Res. 2014;16:203; 10. US Food and Drug Administration. Letter.

http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/20896ltr.pdf. Accessed January 29, 2016.11. US Food and Drug Administration. Letter.

http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/201532s000ltr.pdf. Accessed January 29, 2016; 12. US Food and Drug Administration. Letter

http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021660ltr.pdf. Accessed January 29, 2016. 13.PrIBRANCETM (palbociclib). Product Monograph. Pfizer Canada Inc. November, 16,2017. 14. Kisqali TM

(ribociclib) product monograph, March 1st 2018

TIMELINE OF HR+ MBC TREATMENTS*

Understanding of estrogen, ER, and resistance5

Role of cyclin D1 and CDK4/66,7

Role of PI3K8 and mTOR9

1990 2000 2010

1997Letrozole

NOC2

2000Exemestane

NOC2

2004Fulvestrant

NOC2 2015Palbociclib

US approval

2009Bevacizumab2,3

LapatinibNOC

2020

1973Tamoxifen EU

approval1

Clinical development of new targeted therapies4

2013Everolimus

NOC2

2011Bevacizumab

NOC withdrawn3

18

2016Palbociclib

NOC/c13

1998Toremifene

NOC2

1996Anastrozole

NOC2

2018 ribociclib

NOC14

Evolution of Breast Cancer

Early-stage breast cancer

Advanced/ metastatic

breast cancer

Neoadjuvanttherapy - Reduce

tumor size prior to surgery + reduce risk of recurrence

Adjuvanttherapy –

Reduce risk of recurrence after

surgery

Goal: curative treatment Goal: slow progression and maintain QOL

Palliative Therapy -Prolong survival and

control disease symptoms

20-30% will progress to advanced disease, many ≥2

years following adjuvant therapy

5-10% of BC diagnosis

Cheng, Y.C. & Ueno, N.T. Breast cancer (Tokyo, Japan) 19, 191-199 (2012). Kennecke, H., et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 28, 3271-3277 (2010).

Lobbezoo, D.J., et al. British journal of cancer 112, 1445-1451 (2015).

Chemotherapy: Acute side effects of Adjuvant chemotherapy for early-breast cancer

• Adjuvant chemotx = improvement in both DFS and OS

• Routinely administered for women with early-breast cancer

• However: visit to ER for all causes and associated to serious side effects

• Major reasons requiring hospitalization or ER visit are multiples

Chemotherapy: Taxanes

• Taxol/Taxotere/Abraxane

• Used frequently in early breast cancer

• Neurotoxicity***: taxol=motor + sensory peripheral neuropathy

• Dose and schedule-dependent and CUMULATIVE

• PN with taxol ad 30% severe grade

• PN with taxotere ad 15-20% severe grade

• ***Early recognition;delay/dose reduction

Chemotherapy:Taxanes

• Sx improve slowly after discontinuation (weeks/months)

• Sometime never improve (DB/R-OH)

• Taxol may also cause an acute pain syndrome: 1st few days after Tx with diffuse aching; legs/hips/back/widespread pain (challenging vs Gastrofil/Neupogen pain?)

• Gabapentin not clearly demonstrated but should be try

• Duloxetin (Cymbalta) shown to be effective for chemo-induced PN

Chemotherapy: Taxanes

• Musculoskeletal side effects: myalgias/arthralgias

• First 72-96 hrs

• Less common with weekly taxol

• Not dose-related

• Rx: NSAIDs/Antihistamines?

Chemotherapy: Anthracyclines

• Epirubicine/doxorubicine

• Also commonly used in early-breast cancer

• Higher frequency of emesis : antiemetics must be appropiated

• Complete alopecia : scalp-cooling device?

• ***Small number of acute and long-term cardiotoxicity ( see Dr Lee’spresentation)

Common side effects: myelosuppression

• Neutropenia: 10-14 days after Tx ( most patients)

• Usually resolves before the next Tx

• Most regimens used in BC: risk of FN is less than 2%

• However when Taxotere is part of Tx risk ad 20%

• G-CSF = reduce duration of Neutropenia + NF

Common side effects: myelosuppression

• Anemia: very common

• ESA (Aranesp): not recommended= increase the risk of DVT/PE

• Thrombopenia: very uncommon

Common side effects: GI

• No/Vo: less common with antiemetic Tx tailored to the risk of the specificchemo regimen

• Mucositis more frequent when regimen includes 5FU (FEC)

• Rx Oncology Mouthwash/ however plain antifungal like Nystatin not recommended

Common side effects: weight gain!

• Majority of women gain weight during Tx

• Energy imbalances 2 ’ to chemotx; hormonal changes/ changes in adiposity(insuline resistance?)

Common side effects: dermatological toxicity

• Taxanes/anthracyclines: pigmentary changes

• Nail changes/discoloration/nail coming off=taxotere

• Alopecia: Epirubicine/taxanes/cyclophosphamide

Typically after the 2nd cycle

Transient and regrowth occurs after cessation (red.density)

Scalp-cooling device?

Common side effects: sexual/reproductive sideeffects

• Chemotherapy-induced amenorrhea

• Greater effect on follicular development and oocytes depletion

• Complete follicular depletion/permanent ovarian failure

• Temporarily vs permanent amenorrheic during Tx

-risk greater for women over 40 yo

-ovarian failure is less often reversible in older women

-usually ovarian function (menses) returnes in 50% of women

younger than 40 yo but only in 10% of women over 40 yo

Common side effects: sexual/reproductive

• Chemotherapy mostly associated with ovarian failure:

Cyclophosphamide (FEC orTC) ad 70%

Taxanes mixed results

Common side effects: menopausal symptoms

• Hot flashes/vaginal dryness/dyspareunia/sleep problem

• Most are vasomotor Sx; premature cessation of ovarian function

• Systemic estrogen replacement should not be use

• Non-estrogen Tx is recommanded: gabapentin, venlafaxine, oxybutynin

• Acupuncture?

Common side effects: menopausal symptoms• Vaginal atrophy/dryness: vaginal estrogen should not be use however it is a

case by case discussion

-absorption is very low

-ok with tamoxifen not with AI?

1st line TX: water or silicone-based lubricants

Intrarosa: vaginal prasterone safe also with AI?

Common side effects: contraception

• WHO guidelines: no hormonal contraception in women with a current or past Hx of BC

• Usually: codom.diaphragm,copper IUD

• However Mirena ( Levonorgestrel-progestine hormone) could be use ?Whenon Tam. Systemic absorption of hormone is low

FERTILITY AND PREGNANCY AFTER BC

• Pregnancy is safe

• Pregnancy does not appear to compromise survival regardless of hormonal receptors

• Prior BC Tx do not increase the risk of congenital malformation

• Tamoxifene could be teratogenic= wait at least 3 months from cessation of TAM before attempting pregnancy

• For those who received 1 year of Herceptin= should utilize an effective contraception for at least 7 months after the end: oligohydramnios

Hormonotherapy: definition of menopause

*Endocrine options for Tx depend whether or not a woman is in menopause

*Premenopausal at Dx, if treated with chemo, amenorrhea is not a reliableindicator of menstrual status

NCCN: definition of menopause

• Women over 60 y.o

• Women less than 60 y.o if: - bilateral oophorectomy

- not any menstrual periods x 12 months or

more in the absence of TAM.,Chemo or

Ovarian Supp. + serum estradiol is in the

Postmeno. range

-Amenorrheic on TAM + FSH + Estradiol=

Post-meno. range

Hormonotherapy: Tamoxifen

• Selective estrogen receptor modulator-SERM

• Inhibits by competitive antagonism of the ER

• Tx of choice for Premeno + Postmeno not candidates for AI

• Increase risk of DVT/PE

• Increase risk of Uterine Ca 4% vs 1% Placebo (women over 50 yo)

• Fatty liver disease

• Hot Flashes/vaginal discharge/sexual dysfunction

Hormonotherapy: Aromatase inhibitors

• AIs inhibiting Aromatase

• Aromatase is responsible for peripheral conversion of androgens to estrogens

• AIs improved outcomes for Postmeno/inactived in Premeno

Hormonotherapy: AIs

• Associated with musculoskeletal side effects: carpal tunnel syndrome,jointpain,bone pain and stifness ad 20-70%

• However ad 50% were having preexisting M-S disorder (arthrosis/morningstiffness)

• 1/3 of women may not complete 5 y course of adjuvant AI

• 10-20% discontinuation

• Decreased estrogen levels?

Hormonotherapy: AIs

• Exercise

• NSAIDS

• If no improvement: we stop AI x 2-8 weeks and then begin a different AI

• However 40% only are able to continue on another AI

• Acupuncture?

• Tamoxifen

Hormonotherapy:AIs

• No one AI is preferred over another

• Minimum duration of 5 yrs ( like TAM), however selection of patients for extended Tx based on: original Px,side effects and potential toxicity

Hormonotherapy: AIs

• Increase risk of vaginal sx/sexual dysfunction

• Reduced vaginal lubrication/ dyspareunia

• *** should be informed about these potential adverse ffects

• AIs appear to be associated with a long-term increased risk of CV disease VS Tam: risks-benefits should be individualized in this population

Hormonotherapy: AIs

• Cognitive problems

• Forgetfullness and poor sleep

• Hair loss

• Higher risk of osteoporosis/fractures/hyperlipidemia

• However lower risk of DVT/PE/Uterine Ca VS TAM

Trastuzumab/Herceptin

• Improves outcomes in BC H-2-N +

• Absolute risk reduction of death 15%

• However: risk of congestive heart failure, LVEF declines

• Overall incidence of cardiotoxicity 1-4%

• Reversible if detected early and responds well to Tx (cardio-oncology!)

• Routine cardiac monitoring is recommanded

Conclusions

• Breast cancer is a curable cancer for most women

• Unfortunately cure has a price… resilience ?

• With pronostic tools like Oncotype Dx less women will need adjuvant treatments of chemotherapy; however more hormonotherapy will be prescribe (you werewarned!)

• Family physicians, GPOs, NPs should be confortable in the management of the most common side effects associated with the adjuvant hormonotherapy

QUESTIONS?