1. Update on Common Malignancies in Women: Breast and Cervical Cancers
Dina Dumercy, Pharm.D., BCOP
Oncology IT Pharmacist
Memorial Healthcare System
Miramar, Florida

2. 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

3. 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

4. Cancer Statistics
About 1, 529, 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, Atlanta: American Cancer Society; 2010.

5. Estimated New Cases and Death By Sex

6. 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?

7. 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.

8. Carcinogenesis
(Permission requested)

9. 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

10. Breast Cancer
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)

11. Risk Factors Female gender Increasing age Early menarche
Late Menopause
Older age at first childbirth
Hormone replacement therapy
Chest wall irradiation
Benign 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

12. Normal Risk Breast Cancer Screening
NCCN Guidelines Version Breast cancer Screening and Diagnosis

13. Breast Cancer Increased Risk
NCCN Guidelines Version Breast cancer Screening and Diagnosis

14. Increased Risk Breast Cancer Screening
NCCN Guidelines Version Breast cancer Screening and Diagnosis

15. 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

16. 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< )
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 4 yrs
Risk of IBC and ER+ IBC reduced by 66% and 76%, 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): Vogel, VG. JAMA 2006;295(23):

17. Breast Cancer Work-up History and Physical
Diagnostic bilateral mammogram +/- ultrasound
Pathology review (ER/ PR/ HER2 status/ Histology, etc)
MRI (if necessary)
Additional studies based on symptoms and stage
Bone scans
CT/ PET/ Chest Imaging/ MRI

18. Breast Cancer Staging

19. Breast Cancer Histopathologic Types

20. Treatment Approach Surgery Radiation Chemotherapy Biological therapy
Endocrine therapy
Treatment of Breast cancer is determined by prognostic and predictive factors and patient preference
Histology, TNM status, PS, pathology, age, co-morbidities, menopausal status

21. 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 first
2 21 Gene RT-PCR Assay to determine recurrence risk score to assist in treatment decision, must be done within
3 Triple negative breast cancer

22. Adjuvant Endocrine Therapy

23. Adjuvant chemotherapy
AC-> Paclitaxel weekly or Docetaxel Q3W +/- T
Dose dense AC -> Paclitaxel Q2W
TAC
FEC/ CEF-> Docetaxel Q3W or Paclitaxel weekly+/- T TC EC
CMF
FAC/ CAF
TCH (Docetaxel/ Carboplatin/ Trastuzumab)

24. CEF vs. EC/T vs. AC/T
N= 2104
Endpoints: RFS, OS, toxicity as assessed by the NCI Common Toxicity Criteria and QOL
Interim analysis for recurrence-free survival (RFS) at median follow-up of 30.4 mos
Burnell, M. et. al. J Clin Oncol January 1; 28(1): 77–82.

25. Results- Toxicity

26. Weekly vs Q3W Taxanes
N= 4950
AC->Paclitaxel Q3w vs. weekly vs. Docetaxel Q3w vs. Weekly
Endpoints
DFS OS
Exploratory Analysis
Impact of treatment by HER2 status
Soprano, JA et. al. N Engl J Med 2008; 358:

27. Results

28. Results More neuropathy in the paclitaxel weekly arm
Increased Neutropenia and infection in Docetaxel Q3w arm

29. Recurrent or metastatic disease

30. 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

31. Combination Anti- HER2 Therapy
Lapatinib + Trastuzumab vs. Lapatinib alone
PFS ( [HR] = 0.73; 95% CI, 0.57 to 0.93; P = .008)
CBR (24.7% v 12.4%; P = .01) CR+PR+SD >24 weeks
OS (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%)

33. 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 Chemo
Capecitabine+ Bev vs Capecitabine
Tax 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: (2007). 2 Miles, D. Cancer Res. 69 (Suppl. 3), 495S (2009). 3 Robert, N. J. Clin. Oncol. 29, 1252–1260 (2011).

34. 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

35. 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

36. 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

37. 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 Amgen Inc.

38. Denosumab ADR Severe Hypocalcemia Severe Hypophosphatemia ONJ
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 Invasive Breast Cancer

39. 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

40. Cervical Cancer 3rd most common cancer World wide
78% of cases in developing countries
2nd most frequent cause of cancer death in females

41. Cervical Cancer Risk Factors
Persistent HPV most important contributing factor
Smoking
Parity
Contraceptive use
Early onset of coitus
Multiple sexual partner
History of sexual transmitted disease
Chronic Immunosuppression

42. 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 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

43. Human Papillomavirus Types and Disease Association
mucosal/genital(~40 types)
nonmucosal/cutaneous
(~60 types)
high-risk types
16, 18, 31, 45
(and others)
low-risk types
6, 11
(and others)
skin warts (hands and feet)
low grade cervical abnormalities
cancer precursors
anogenital cancers
low grade cervical
abnormalities
genital warts
laryngeal papillomas

44. 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

45. Natural History of HPV Infection

46. 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

47. 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

48. CDC Vaccines and Immunization Contact Information
Telephone CDC.INFO
Website

49. 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

50. 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

51. 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

52. HPV Vaccines
Quadrivalent HPV vaccine protect against certain types of HPV (6, 11, 16, 18)
Bivalent vaccine protects against HPV 16 and 18
Vaccine most effective if started before intercourse
FDA approved for 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 years

53. 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

54. Cervical Cancer Staging

55. 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

56. Treatment Continued Metastatic Disease Surgical resection +/- IORT
Radiation +/- Chemo
Chemotherapy (Cisplatin Based)

57. GOG 169 N= 264 Cisplatin+ Paclitaxel vs Cisplatin alone RR= 36% vs 19%
PFS= 4.8 mos vs 2.8 os (P= 0.001)

58. GOG 179 n= 294 Randomized Phase III trial
Cisplatin + Topotecan vs Cisplatin
RR 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 QOL
First study to show survival advantage over single agent cisplatin

59. 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
important
Closed 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:

60. GOG 204 Results
Monk BJ et al. J Clin Oncol 2009; 27:

61. 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:

62. Cervical Cancer Surveillance
Based on NCCN consensus
Cervical cytology Q3- 6 mos x 2 years, then Q6 mos for 3- 5 years, then annually
Careful surveillance due to increased risk for secondary cancers at and near radiated sites

63. Role of a pharmacist Drug Interaction screening Supportive Care
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

64. The role of a pharmacist
Patient education on where to get additional information
American Cancer Society
National Cancer Institute
National Comprehensive Cancer Network
Center for Disease Control and Prevention
Patient Assistance Programs
NeedyMeds
RxAssist
Prior Authorizations or recommending therapeutic substitutions to maximize benefits

65. QUESTIONS?