DINA DUMERCY, PHARM.D., BCOPONCOLOGY IT PHARMACIST

MEMORIAL HEALTHCARE SYSTEMMIRAMAR, FLORIDA

Update on Common Malignancies in Women:

Breast and Cervical Cancers 

Disclosures

Dina Dumercy, Pharm.D. declares no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria

Objectives

Upon completion of this program, the participant will be able to:

Describe the prevalence and diagnosis of breast and cervical cancers

Recommend the latest screening recommendations for breast and cervical cancers

Review guidelines for appropriate selection of therapy

Describe strategies that pharmacists can use to enhance patient compliance to therapy

Cancer Statistics

About 1, 529, 560 new cancer cases are expected to be diagnosed

569,490Americans are expected to die of cancer (more than 1,500 people a day)

Cancer is the second most common cause of death in the US, exceeded only by heart disease

In the US cancer accounts for nearly 1 of every 4 deaths

African Americans are more likely to develop and die from cancer than any other racial group

American Cancer Society. Cancer Facts and Figures, 2010. Atlanta: American Cancer Society; 2010.

Estimated New Cases and Death By Sex

Commonly Asked Questions

What is cancer?Is there anything to prevent cancer?What is the best treatment for cancer?Where can I get more information on the

guidelines for treatment?What are the risk factors for developing

cancer?They tell me I have cancer, what should I do?

What is cancer?

A group of diseases characterized by uncontrolled growth of abnormal cells, when this spread or growth is uncontrolled it may lead to death.

A multistep process in which an accumulation of genetic events with a single cell line leads to a progressively dysplastic cellular appearance, deregulated cell growth and finally evident disease.

Carcinogenesis

http://www.dkfz.de/en/tox/images/scheme-cancer-prevention.jpg (Permission requested)

What are the risk factors for Cancer?

Genetics Family History Genetic testing

Lifestyle Tobacco Exercise Diet

Environmental Radiation Asbestos

Personal History Cancer Pre-malignant disease Infections Medications

•207, 090 NEW CASES OF INVASIVE BREAST CANCER (IBC) WERE EXPECTED TO OCCUR IN WOMEN IN THE US DURING 2010•ABOUT 1,970 NEW CASES ARE EXPECTED IN MEN•54,010 NEW CASES OF IN SITU BREAST CANCERS ARE EXPECTED (85% DUCTAL CARCINOMA IN SITU)•LIFETIME RISK OF DEVELOPING BREAST CANCER IS 12.3% (1 IN 8 WOMEN)

Breast Cancer

Risk Factors

Female genderIncreasing ageEarly menarcheLate MenopauseOlder age at first

childbirthHormone

replacement therapyChest wall irradiationBenign proliferative

breast disease

Family history Early onset breast

cancer Family with known

mutation 2 or more 1st degree

relatives or 1 with Dx before 50 yrs of age

Genetic mutations (i.e.. BRCA1 or 2, PTEN, p53)

Ovarian/ Fallopian/ peritoneal cancers

Normal Risk Breast Cancer Screening

NCCN Guidelines Version 1.2011 Breast cancer Screening and Diagnosis

Breast Cancer Increased Risk

NCCN Guidelines Version 1.2011 Breast cancer Screening and Diagnosis

Increased Risk Breast Cancer Screening

NCCN Guidelines Version 1.2011 Breast cancer Screening and Diagnosis

Breast Cancer Risk Assessment

Patient with moderate or high risk factors should be seen for genetics counseling

Risk reduction counseling should occur for all women with high lifetime risk

Surgical risk reduction strategies generally reserved for patients with strongly predisposing gene mutation

Risk Reduction agents Tamoxifen and Raloxifene are options after a discussion on the relative risk reduction, adverse reactions and benefits

Risk Reduction agents

Trials Outcome

NSABP P-1(BCPT)(n=13,388)

Placebo vs. Tamoxifen 20 mg/d x 5 y

•Reduce risk of IBC by 49% (P<0.00001)•Risk of IBC reduced by 56% and 86% in LCIS and atypical hyperplasia, respectively

CORE(n=5,213)

Placebo vs. Raloxifene 60 or 120 mg

•Reduce risk of IBC by 66% @ 4 yrs•Risk of IBC and ER+ IBC reduced by 66% and 76%, respectively @ 8 yrs

NSABP P-2(STAR)(n=19,747)

Tamoxifen 20 mg vs. Raloxifene 60mg daily for 5 years

•@8 years follow-up Raloxifene 76% is as effective as Tamoxifen in reducing IBC risk•Raloxifene is as effective as Tamoxifen in reducing risk in Atypical hyperplasia

Fisher, B. CA Cancer J Clin 1999;49(3):159-77. Vogel, VG. JAMA 2006;295(23):2727-41.

Breast Cancer Work-up

History and PhysicalDiagnostic bilateral mammogram +/-

ultrasoundPathology review (ER/ PR/ HER2 status/

Histology, etc)MRI (if necessary)Additional studies based on symptoms and

stage Bone scans CT/ PET/ Chest Imaging/ MRI

Breast Cancer Staging

Breast Cancer Histopathologic Types

Treatment Approach

SurgeryRadiationChemotherapyBiological therapyEndocrine therapyTreatment of Breast cancer is determined by

prognostic and predictive factors and patient preference Histology, TNM status, PS, pathology, age, co-

morbidities, menopausal status

Adjuvant Treatment

ER/ PR (+) HER2 (-) Adjuvant Endocrine +/- Adjuvant Chemotherapy

1, 2

ER/ PR(+) HER2 (+) Adjuvant Endocrine +/- Adjuvant Chemotherapy + Trastuzumab

1

ER/ PR (-)/ HER2 (+) Adjuvant chemotherapy + Trastuzumab

ER/PR (-)/ HER2 (-) Adjuvant chemotherapy 3

1 Endocrine Tx and Chemo given sequentially with Chemo given first2 21 Gene RT-PCR Assay to determine recurrence risk score to assist in treatment decision, must be done within3 Triple negative breast cancer

Adjuvant Endocrine Therapy

Adjuvant chemotherapy

AC-> Paclitaxel weekly or Docetaxel Q3W +/- TDose dense AC -> Paclitaxel Q2WTACFEC/ CEF-> Docetaxel Q3W or Paclitaxel

weekly+/- TTCECCMFFAC/ CAFTCH (Docetaxel/ Carboplatin/ Trastuzumab)

CEF vs. EC/T vs. AC/T

N= 2104Endpoints: RFS, OS, toxicity as assessed by

the NCI Common Toxicity Criteria and QOLInterim analysis for recurrence-free survival

(RFS) at median follow-up of 30.4 mos

Burnell, M. et. al. J Clin Oncol. 2010 January 1; 28(1): 77–82.

Results- Toxicity

Weekly vs Q3W Taxanes

N= 4950AC->Paclitaxel Q3w vs. weekly vs. Docetaxel

Q3w vs. WeeklyEndpoints

DFS OS

Exploratory Analysis Impact of treatment by HER2 status

Soprano, JA et. al. N Engl J Med 2008; 358:1663-1671.

Results

Results

More neuropathy in the paclitaxel weekly arm

Increased Neutropenia and infection in Docetaxel Q3w arm

Recurrent or metastatic disease

Recurrent or Metastatic Disease

Preferred Single Agents Doxorubicin Epirubicin Paclitaxel Docetaxel Capecitabine Gemcitabine Vinorelbine Eribulin Paclitaxel

+Bevacizumab

Preferred Combinations AC CAF/FAC FEC AT Docetaxel/ Capecitabine Gemcitabine/ Paclitaxel Trastuzumab + Other 1st

line agents Trastuzumab or

Lapatininb+Capecitabine Trastuzumab + Lapatinib

Combination Anti- HER2 Therapy

(N = 296)Lapatinib + Trastuzumab vs. Lapatinib alonePFS ( [HR] = 0.73; 95% CI, 0.57 to 0.93; P = .008)CBR (24.7% v 12.4%; P = .01) CR+PR+SD >24

weeksOS (HR = 0.75; 95% CI, 0.53 to 1.07; P = .106). ORR (10.3% v 6.9; P = .46). Most frequent ADR: diarrhea, rash, nausea, and

fatigue; diarrhea was higher in the combination arm (P = .03).

Symptomatic cardiac events was low (2% vs 0.7%)

The Role of Bevacizumab

PFS

Paclitaxel + Bev vs. Paclitaxel 11.8 vs 5.9 mos (P<0.001)

Docetaxel + Bev vs. Docetaxel 10.1 vs. 8.2 mos(P<0.006)

Ribbon-1 Bev ChemoCapecitabine+ Bev vs CapecitabineTax or Anthracycline arm combo

8.6 vs 5.7 mos (P<0.0002)9.2 vs 8.0 mos (P<0.0001)

•No Increase in OS or QOL when analyzed alone or in meta analysis•Modest increase in PFS with the greatest increase seen in combination with Paclitaxel•FDA Reversed approval in breast cancer

1Miller, K. N Engl J Med. 357:2666-2676 (2007). 2 Miles, D. Cancer Res. 69 (Suppl. 3), 495S (2009). 3 Robert, N. J. Clin. Oncol. 29, 1252–1260 (2011).

Eribulin

Microtubular inhibitor FDA approved in November 2010 for Metastatic breast cancer after 2 lines of therapy

Phase III open-label, randomized, multicenter study(n=762)

2-5 prior CT (≥2 for advanced disease), including an anthracycline and a taxane, unless contraindicated

Pts were randomized 2:1 to E 1.4 mg/m2 2-5 min IV bolus on days 1 and 8 of a 21-day cycle or treatment of physician's choice (TPC)

Endpoint: OS; ORR, PFS, DOR

Eribulin

Results of Phase III OS: 13.1 vs 10.6 mos. (HR 0.81, 95% CI 0.66 to

0.99(P=0.041) No difference in TTP Objective response rate by the RECIST criteria

was 11% (95% CI:  8.6%, 14.3%) Median response duration was 4.2 months (95%

CI: 3.8, 5.0 months) Common ADR: neutropenia, anemia,

asthenia/fatigue, alopecia, peripheral neuropathy (DLT), nausea, and constipation

Denosumab

XGEVA approval to prevent skeletal-related events in cancer patients with solid tumors and bone metastases

Human monoclonal antibody that binds to RANK ligand, a protein found on osteoclasts and involved in bone breakdown

•Randomized, double-blind, phase III clinical trial in women with bone metastases from breast cancer •Denosumab 120 mg SQ monthly vs. Zoledronic acid 4 mg IV monthly

Denosumab Results

•Non-inferiority Trial•Delayed the time to first SRE•Overall survival and progression-free survival were similar between arms

Xgeva™ (denosumab)Prescribing information. 2010.Amgen Inc.

Denosumab ADR

Severe Hypocalcemia Corrected serum calcium <7 mg/dL or < 1.75 mmol/L) -3.1% Patients with a creatinine clearance less than 30

mL/min or receiving dialysis are at greater risk of severe hypocalcemia

Severe Hypophosphatemia Serum phosphorus <2 mg/dL or < 0.6 mmol/L -15.7%

ONJ Perform an oral examination and appropriate

preventive dentistry prior to the initiation

Common ADR fatigue/asthenia, and nausea

NCCN Guidelines Version 2.2011 Invasive Breast Cancer

Denosumab Summary

Denosumab, Zoledronic acid or amidronate (all with Calcium and vitamin D) should be given in addition to Chemo or endocrine therapy if bone mets is present, expected survival is > 3 months, and renal function is adequate

3RD MOST COMMON CANCER WORLD WIDE78% OF CASES IN DEVELOPING COUNTRIES

2ND MOST FREQUENT CAUSE OF CANCER DEATH IN FEMALES

Cervical Cancer

Cervical Cancer Risk Factors

Persistent HPV most important contributing factor

SmokingParityContraceptive useEarly onset of coitusMultiple sexual partnerHistory of sexual transmitted diseaseChronic Immunosuppression

HPV and Cervical Cancer

Most common sexually transmitted virus in the US

At least 50% of sexually active people will have HPV at some point in their lives

HPV Cause epithelial proliferations at cutaneous and mucosal surfaces

20 million Americans 15- 40 years of age (15% of population)are currently infected

There are more than 100 types of the virus and about 40 types of HPV are associated with genital HPV

www.cdc.gov/HPV/cancer.html

Human Papillomavirus Types and Disease Association

nonmucosal/cutaneous(~60 types)

skin warts

(hands and feet)

mucosal/genital(~40

types)

high-risk types16, 18, 31, 45(and others)

low-risk types6, 11

(and others)

•low grade cervical abnormalities•cancer precursors•anogenital cancers

•low grade cervical abnormalities•genital warts•laryngeal papillomas

http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/Slides/HPV11.ppt

HPV types and disease association

HPV-16 and HPV-18 are the most prevalent of the oncogenic types Associated with cervical, vulvar and vaginal cancers

HPV- 6 and HPV-11 "low-risk" types can cause genital warts and usually benign (abnormal but non-cancerous) changes in the cervix

The high efficacy of the vaccines may dramatically decrease cervical cancer, preventing up to 70% of newly diagnosed cases

Natural History of HPV Infection

Screening Recommendations

NCCN adopted the American College of Obstetricians and Gynecologists screening recommendations

Screening should begin at 21 years of age regardless of sexual intercourse status Every 2 years between 21 and 29 years of age

Adolescents who are immunocompromised (HIV, steroid use, post transplant, etc.) should also have cervical cytology screened

Both liquid based and conventional methods of cervical cytology are acceptable

Screening Recommendations

Combination of cytology and HPV DNA testing is appropriate for women greater than 30 years old Women who are low risk with both negative result should

be screened every 3 years HPV DNA testing is not indicated in women < 21 years old

Women 30 year and older who had 3 consecutive negative cervical cytology screening test, not immunocompromised, no history of cervical intra-epithelial neoplasia (CIN), not HIV infected, and were not exposed to DES in utero may extend the interval between cervical cytology to every 3 years

CDC Vaccines and Immunization

Contact Information

Telephone 800.CDC.INFO

Email nipinfo@cdc.gov

Website www.cdc.gov/vaccines

Screening Recommendation

Women who have been immunized against HPV-16 and HPV-18 should be screened by the same schedule as non-immunized

Annual gynecologic examination may still be appropriate even if cervical cytology is not tested at each visit

Women treated in the past or CIN, or cancer including status post hysterectomy should have annual screening for at least 20 years after surveillance

Screening Recommendation

Screening can be discontinued; In women who have had a total

hysterectomy for benign indication and have no history of high grade CIN

Women between 65 and 70 years of age and older with 3 or more negative cytology test in a row and no abnormal test in the past 10 years

HPV DNA Testing

HPV high risk DNA test- detects whether any of the 14 high risk (oncogenic) types of HPV are present, does not indicate which type is present

HPV 16/18- detects whether HPV 16 or 18 is present, used together with the HPV high-risk DNA test

Hybrid Capture 2 HPV DNA test- asses whether women are positive for any of 13 high-risk, false- positive results due to cross reactivity with non-oncogenic subtypes

HPV Vaccines

Quadrivalent HPV vaccine protect against certain types of HPV (6, 11, 16, 18)

Bivalent vaccine protects against HPV 16 and 18Vaccine most effective if started before

intercourse FDA approved for 9- 26 and 10 – 25 year old

females respectively to prevent cervical cancer and precancerous lesions due to HPV

Not clear how long immunity is present after vaccination, data suggest 5- 10 years

Diagnosis of Cervical cancer

Diagnosis often from cervical cytology, PAP smears and biopsies (Conization used to determine invasiveness)

Colposcopy, and colposcopy directed biopsies is the primary method for evaluating abnormal cervical cytology

CT scans, MRI, PET-CT and surgical staging are used to guide treatment

Cervical Cancer Staging

Cervical Cancer Treatment

Surgery for lower stage disease Observation is appropriate for lower stage (IA2, IB1,

IIA1) and no risk factors and negative nodes Adjuvant XRT indicated if large primary tumor, LVSI, deep

stromal invasion, +LN, +Sx Margins, and + parametrium

Chemo-radiation for higher stages or patients who are not candidates for hysterectomy Cisplatin based chemotherapy Chemo/XRT have shown a 30-50% decrease in risk of

death compared to XRT alone 3 trials have shown improved PFS and OS with

Chemo/XRT

Treatment Continued

Metastatic Disease Surgical resection +/- IORT Radiation +/- Chemo Chemotherapy (Cisplatin Based)

GOG 169

N= 264Cisplatin+ Paclitaxel vs Cisplatin aloneRR= 36% vs 19%PFS= 4.8 mos vs 2.8 os (P= 0.001)

GOG 179

n= 294Randomized Phase III trialCisplatin + Topotecan vs CisplatinRR 27% vs 13% (P=0.004)PFS 4.6 mos vs 2.9 mos (P=0.014)Median survival 9.4 mos vs 6.5 mos (P= 0.017)Increase marrow suppression but no decrease

in QOLFirst study to show survival advantage over

single agent cisplatin

GOG 204

N= 513 Women with advanced (stage IVB), recurrent, or persistent cervical cancer

Cis/ Topotecan, Cis/ Gemcitabine, Cis/Vinorelbine, vs Cis/ Paclitaxel

Survival was the primary end point with a 33% improvement relative to PC considered

importantClosed early due to non-superiority of other

regimens

Monk BJ et al. Phase III Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB, Recurrent, or Persistent Cervical Carcinoma: A Gynecologic Oncology Group Study. J Clin Oncol 2009; 27:4649-4655.

GOG 204 Results

Monk BJ et al. J Clin Oncol 2009; 27:4649-4655.

GOG 204

Advantage seen in women of Hispanic origin and in recurrent disease PFI of 30+ months

Monk BJ et al. J Clin Oncol 2009; 27:4649-4655.

Cervical Cancer Surveillance

Based on NCCN consensusCervical cytology Q3- 6 mos x 2 years, then

Q6 mos for 3- 5 years, then annuallyCareful surveillance due to increased risk for

secondary cancers at and near radiated sites

Role of a pharmacist

Drug Interaction screening Complementary and Alternative Medications can be

prevalent in cancer patients

Supportive Care Pain Management Anti-coagulation Monitoring Side Effect Management

Compliance and Adherence Monitoring Increased use of oral chemotherapy medications Endocrine therapies

The role of a pharmacist

Patient education on where to get additional information American Cancer Society www.cancer.org National Cancer Institute www.cancer.gov National Comprehensive Cancer Network

www.nccn.com Center for Disease Control and Prevention www.cdc.gov

Patient Assistance Programs NeedyMeds www.needymeds.com RxAssist www.rxassist.org Prior Authorizations or recommending therapeutic

substitutions to maximize benefits