1. Locally Advanced and Metastatic Disease
Breast Cancer
Locally Advanced and Metastatic Disease
C. Legler MD FRCPC
September 30, 2005

2. Locally Advanced and Metastatic Breast Cancer
Overview:
Principles of neoadjuvant chemotherapy for locally advanced and inflammatory breast cancer
Systemic therapy of metastatic breast cancer
Chemotherapy
Hormonal agents
Biologic agents
Bisphosphonates
Rationale for selection of treatment in metastatic disease
chemotherapy vs. hormonal agents
Ideal first line agents?

3. Locally Advanced Breast Cancer
Definition: breast cancer, without distant metastatic spread, which is unresectable due to
Satellite skin nodules
Extensive regional lymph node involvement
Fixation to skin or chest wall
Inflammatory breast cancer

4. Locally Advanced Breast Cancer
Combined modality treatment is the standard of care for locally advanced breast cancer.
Neoadjuvant chemotherapy
Goals are to improve resectability of the tumour and to increase rates of breast conserving treatment.
Locoregional therapy
Surgery, or radiotherapy, or both.

5. Locally Advanced Breast Cancer
Response rates to neoadjuvant chemotherapy:
Major responders: %
Clinical complete responders: 8-63%
Pathologic complete responders: 3-30%
A major response to chemotherapy is associated with improved disease-free and overall survival.

6. Locally Advanced Breast Cancer
Survival is related to axillary lymph node status after neoadjuvant chemotherapy.
Positive nodes 5-year overall survival % % %
> %

7. Locally Advanced Breast Cancer
Survival is related to response of primary tumour to neoadjuvant chemotherapy.
Author
Median follow-up, years
Survival, patients with complete response
Survival, patients with partial response
Method of response assessment
Eltahir, 1998 5
74% overall survival
36% overall survival
Clinical response
Kuerer, 1999
89% overall survival
64% overall survival
Pathologic response
Bonnadonna,1998 8
86% disease-free survival
56% disease-free survival

8. Locally Advanced Breast Cancer
Duration of neoadjuvant chemotherapy
Optimal duration of treatment is not known.
Rule of thumb: “treat until maximal response.”
May require from 2-8 treatments, depending on rapidity of response.
Patients should be assessed by multidisciplinary team after every 2 cycles of chemotherapy to determine optimal timing of surgery.

9. Locally Advanced Breast Cancer
Ideal neoadjuvant chemotherapy regimen has not been identified.
Anthracycline based (epirubicin or adriamycin) chemotherapy is often used at start (AC, CAF, FEC).
Taxanes (taxol, taxotere) are also extremely effective and have been shown to increase the rate of pathologic complete responses.

10. Locally Advanced Breast Cancer
Impact of Taxanes in Neoadjuvant Chemotherapy.
TAX-301 trial
162 patients, randomly assigned to pre-operative CAVP X 8 cycles vs.
CAVP x 4 then Taxotere X4
5 year overall survival:
CAVP X 8: 78%
CAVP X 4 + Taxotere X 4: 97%

11. Locally Advanced Breast Cancer
Impact of Taxanes in Neoadjuvant Chemotherapy, continued
NSABP B-27
Preoperative AC X 4 vs
preoperative AC X 4 plus Taxotere X 4
pathologic CR negative nodes
AC X4 14% 51%
AC X4,Tax X4 26% 58%

12. Locally Advanced Breast Cancer
Consensus for chemotherapy
Give 4 cycles of anthracycline based or taxane chemotherapy.
Assess response:
If CR or near CR: proceed to definitive local therapy, then 4 cycles of non cross-resistant regimen.
If less than “near complete response”: proceed to 4 cycles of non cross-resistant chemotherapy, then definitive local therapy.

13. Locally Advanced Breast Cancer
Consensus for chemotherapy, continued:
A total of 8 chemotherapy cycles should be given (anthracycline x 4, taxane x 4).
All 8 cycles may be given preoperatively, or they may be split between preoperative and postoperative chemotherapy.
e.g. Anthracycline x4 then surgery then Taxane x4.
Or Anthracycline x4 then Taxane x4 then surgery.
Or Taxane x4 then surgery then Anthracycline x4.
Or Taxane x4 then Anthracycline x4 then surgery.

14. Locally Advanced Breast Cancer
Role of Herceptin (trastuzumab):
Initial reports are encouraging, but use of herceptin cannot be recommended outside of a clinical trial.
Role of High-dose chemotherapy with stem cell support:
No improvement in DFS or OS, with significant increase in toxicity and worsening of quality of life, therefore not recommended.

15. Locally Advanced Breast Cancer
Hormonal Management
Acceptable in Estrogen Receptor and/or Progesterone Receptor positive cancers.
Best used in patients where chemotherapy is relatively contraindicated
Elderly
Poor performance status
Comorbid illness
Patient reluctance to accept chemotherapy

16. Locally Advanced Breast Cancer
Hormonal Management, continued:
Rate of pathologic complete response is greatly diminished.
Rate of breast-conserving treatment is greatly diminished.
Response to treatment is much slower, e.g. 3-9 months.

17. Locally Advanced Breast Cancer
Summary:
Standard of care is multimodality treatment.
Chemotherapy: should contain anthracyclines and/or taxanes and should begin before surgery.
Locoregional therapy: should be performed when a maximal tumour response has been obtained.
Post-operative chemotherapy: should be performed if less than 8 cycles were given pre-operatively, until a total of 8 cycles of chemotherapy have been given.
Hormonal management: is a slower option, and is restricted to ER and/or PR positive tumours.

18. Locally Advanced Breast Cancer
Any questions on systemic treatment of locally advanced or inflammatory breast cancer?

19. Metastatic Breast Cancer
Goals of treatment of metastatic breast cancer:
Cure: not a realistic goal
Few patients have complete responses, and disease free intervals are short.
Prolongation of survival:
5-10% of patients will survive 5 years or more.
2-5% of patients are long-term survivors (>10 years).
Improvement of Quality of Life:
Most patients experience fewer disease symptoms, with manageable treatment side effects.

20. Metastatic Breast Cancer
Numerous treatment options exist:
Chemotherapy: anthracyclines, taxanes, vinorelbine, capecitabine
Hormonal therapies: tamoxifen (Nolvadex), anastrozole (Arimidex), letrozole (Femara), exemestane (Aromasin), megestrol acetate (Megace)
Biologic agents: trastuzumab (herceptin)
Bisphosphonates: pamidronate, zolendronate

21. Metastatic Breast Cancer
Different options can be combined.
Herceptin and chemotherapy.
Hormonal agents and bisphosphonates.
Herceptin, chemotherapy and bisphosphonates.

22. Metastatic Breast Cancer
How is initial therapy selected?
Patient factors: age, comorbid conditions, willingness to accept side effects.
Tumour factors: ER, PR, her-2/neu status.
Course of illness: extent and location of metastases, disease-free interval, pace of spread of metastases.
Treatment factors: adjuvant chemotherapy, adjuvant hormonal agents, adjuvant radiotherapy.

23. Metastatic Breast Cancer
The use of hormonal agents is favoured if:
Tumour is ER and/or PR positive.
Disease-free interval is long.
Few sites of metastases.
Metastases do not involve visceral organs.
Pace of disease progression is slow.
Patient has responded to previous hormonal agents.

24. Metastatic Breast Cancer
Use of hormonal agents, continued
Hormonal agents require 8-12 weeks to determine their efficacy, thus they are not recommended for patients with extensive visceral metastases.
Initial response to hormonal agents is 50-60% is ER/PR positive patients.

25. Metastatic Breast Cancer
The use of chemotherapy is favoured if:
Tumour is negative for ER and PR.
Disease-free interval is short.
Extensive metastases are present, especially visceral disease (liver, lung).
Disease is progressing rapidly.
Patient has not responded to previous hormonal agents.
Initial response to chemotherapy is 50-75%.
No clear advantage of combination regimens over use of sequential single agents.

26. Metastatic Breast Cancer
Hormonal agents:
Tamoxifen:
Mixed estrogen receptor agonist-antagonist.
Can be used in premenopausal and postmenopausal women.
Response rates are 50-60%.
Duration of response may be years.
Toxicities: hot flashes, increased risks of DVT/ pulmonary embolism, endometrial cancer
May be associated with tumour flare reaction in up to 13% of patients.

27. Metastatic Breast Cancer
Hormonal agents, continued:
Aromatase inhibitors:
Anastrozole (Arimidex), non-steroidal
Letrozole (Femara), non-steroidal
Exemestane (Aromasin), steroidal
Method of action: block conversion of adrenal androgens to estrogen in adipose tissue and in the breast.
Use is restricted to postmenopausal women.
Side effects: hot flashes, myalgias/arthralgias, increased risk of osteoporosis, altered lipid profiles.

28. Metastatic Breast Cancer
Hormonal agents, continued:
Aromatase inhibitors:
Anastrozole and Letrozole:
are non-steroidal aromatase inhibitors.
are both superior to Megace in tamoxifen refractory patients.
have similar efficacy to tamoxifen, with fewer side effects.

29. Metastatic Breast Cancer
Hormonal agents, continued:
Aromatase inhibitors:
Exemestane:
is a steroidal aromatase inhibitor.
is superior to Megace, and at least as effective as Tamoxifen.
can be effective in patients who have failed non-steroidal aromatase inhibitors.

30. Metastatic Breast Cancer
Hormonal agents, continued:
Megace (megestrol acetate)
Is a progestin
Before aromatase inhibitors, was considered second-line therapy, after tamoxifen.
May still have activity in some patients who have failed tamoxifen and/or aromatase inhibitors.
Side effects: increased appetite, weight gain, increased risk of DVT/pulmonary embolism.

31. Metastatic Breast Cancer
Sequencing of Hormonal agents in metastatic breast cancer:
Postmenopausal patients:
Anastrozole or Letrozole as first line
Exemestane as second line
Tamoxifen and Megace remain options for third line OR for patients who do not tolerate aromatase inhibitors.
Premenopausal patients:
Tamoxifen as first line
Megace OR aromatase inhibitor with ovarian ablation as second line.

32. Metastatic Breast Cancer
Chemotherapy:
Numerous agents have activity in metastatic breast cancer:
Anthracyclines
Taxanes
Fluoropyrimidines
Vinca alkaloids
Other drugs: cyclophosphamide, methotrexate, gemcitabine

33. Metastatic Breast Cancer
Anthracyclines
doxorubicin (Adriamycin), epirubicin,
mitoxantrone
liposomal-PEGylated doxorubicin (Doxil-Caelyx)
Are among the most active agents in breast cancer (response rate at least 50%)

34. Metastatic Breast Cancer
Anthracyclines (cont’d)
Used in combination with cyclophosphamide, and 5-fluorouracil
Significant toxicities exist
Nausea
Alopecia
Mucositis
Myelosuppression
Cumulative cardiomyopathy
Radiation recall effect

35. Metastatic Breast Cancer
Anthracyclines, cont’d
Cumulative cardiomyopathy is the limiting toxicity in metastatic breast cancer, particularly in patients who received anthracyclines in the adjuvant setting.
Liposomal PEGylated doxorubicin
has less cardiomyopathy, more cutaneous side effects (palmar-plantar syndrome).
Much more expensive than doxorubicin.

36. Metastatic Breast Cancer
Taxanes
Paclitaxel (Taxol)
Docetaxel (Taxotere)
Nanoparticle albumin-bound paclitaxel (Abraxane)
Are the single most active drugs in breast cancer and the most active in adriamycin-refractory patients. (RR = 60%)
Common toxicities include peripheral neuropathy, myalgias, arthralgias and alopecia.

37. Metastatic Breast Cancer
Taxanes, cont’d:
Paclitaxel (taxol)
can induce anaphylactoid reactions, requiring premedication with steroids and antihistamines.
Efficacy and toxicity profile can be improved by weekly administration (as opposed to q3weeks).
Docetaxel (taxotere)
Can induce responses in 25% of patients who are resistant to paclitaxel.
Cumulative toxicities include fluid retention, sclerosis of tear ducts, loss of fingernails/toenails.

38. Metastatic Breast Cancer
Taxanes, cont’d
Nanoparticle albumin-bound paclitaxel (Abraxane)
Novel formulation, does not require Cremophor.
No risk of anaphylactoid reaction, thus no need for steroids.
Better tissue penetration.
Less toxic and more effective than paclitaxel.
Approved in the USA, not yet approved in Canada.

39. Metastatic Breast Cancer
Fluoropyrimidines:
5-fluorouracil:
is commonly used in combinations, such as CMF, CAF, FEC.
Has activity as a single agent, esp. in prolonged infusions, but these regimens are not convenient.
Toxicities: mucositis (stomatitis, enteritis, colitis), hand-foot syndrome, some myelosuppression

40. Metastatic Breast Cancer
Fluoropyrimidines, cont’d
Capecitabine (Xeloda)
Oral 5-FU derivative, given BID X14 days q21days.
Prodrug is activated to 5-FU in tumour cells, mimics a prolonged 5-FU infusion.
Has activity even in patients who are refractory to anthracyclines and taxanes!! (RR=25%)
Dose limiting toxicity is usually hand-foot syndrome.
NOT HEPATICALLY METABOLIZED, thus ideal agent in patients with severe liver dysfunction!

41. Metastatic Breast Cancer
Vinca alkaloids:
Vinorelbine (Navelbine)
Semi-synthetic vinca alkaloid, related to VCR/VBL
Less neurotoxicity, due to diminished binding to axonal microtubules.
Active even in heavily pretreated patients (response rates = 25-50%).
Excellent toxicity profile: no nausea, no alopecia, no mucositis
Well tolerated by elderly, frail patients

42. Metastatic Breast Cancer
Other drugs:
Cyclophosphamide
Methotrexate
Gemcitabine
All have limited activity as single agents, but are useful in combinations with other active drugs
e.g. CMF, CAF, Gemcitabine-Taxol

43. Metastatic Breast Cancer
Biologic agents
Herceptin (trastuzumab)
Humanized mouse monoclonal antibody directed against the her-2/neu protein.
Has activity against breast cancers that strongly overexpress her-2/neu (score= 3+/3).
Has activity as a single agent, even in heavily pre-treated patients.

44. Metastatic Breast Cancer
Herceptin, cont’d
Can be safely administered with taxanes and vinorelbine, with increased response rates (compared to chemotherapy alone).
Cannot be given with adriamycin; response rates increase BUT rate of cardiomyopathy rises to 27%!!!
Patients on herceptin who have received anthracyclines in the past need monitoring for cardiac toxicity.

45. Metastatic Breast Cancer
Bisphosphonates:
Pamidronate (Aredia)
Zolendronate (Zometa)
Given monthly to patients with bone metastases.
Leads to decreased risk of skeletal complications (pain, fractures, need for radiotherapy)
Few toxicities: fever and chills post-infusion, muscle spasms (transient hypocalcemia)
Rare cumulative toxicity: osteonecrosis of the mandible (!)

46. Metastatic Breast Cancer
A rational approach to selecting therapy for patients with metastatic breast cancer:
For patients with bone metastases:
monthly administration of Pamidronate or Zolendronate (regardless of ER/PR/her-2 status)
For patients with ER and/or PR positive breast cancer, with low burden of metastases and slow pace of disease:
start with hormonal agents.
If patient was on a hormonal agent at time of relapse, try to select a non cross-resistant agent.

47. Metastatic Breast Cancer
A rational approach to selecting therapy for patients with metastatic breast cancer:
For patients with ER-negative/PR-negative disease OR for patients with high tumour burden OR with rapid disease progression:
Start with chemotherapy
In anthracycline-naïve patients, use anthracyclines.
In patients who had adjuvant anthracyclines, use taxanes.

48. Metastatic Breast Cancer
A rational approach to selecting therapy for patients with metastatic breast cancer:
For patients with ER-negative/PR-negative disease OR for patients with high tumour burden OR with rapid disease progression:
2nd, 3rd, 4th lines of treatment depend on patient’s previous side effects and current symptoms.
e.g. navelbine contraindicated in patient with abnormal liver function tests; capecitabine would be a safer choice.

49. Metastatic Breast Cancer
A rational approach to selecting therapy for patients with metastatic breast cancer:
For patients with her-2/neu 3+ disease:
Herceptin should be given with taxane or vinorelbine chemotherapy.
Herceptin can be given as a single agent even in heavily pre-treated patients.
Herceptin as a single agent can be given as “maintenance” therapy after “inducing” a major reduction in tumour burden with herceptin-chemo combination.

50. Metastatic Breast Cancer
Any questions about systemic treatment of metastatic breast cancer?

51. Locally Advanced and Metastatic Breast Cancer
Summary:
For locally advanced breast cancer:
Assessment by a multidisciplinary team (surgical, radiation and medical oncologists) is essential.
Neoadjuvant chemotherapy is used to improve resectability.
Anthracyclines and taxanes are key components of neoadjuvant chemotherapy.

52. Locally Advanced and Metastatic Breast Cancer
Summary, cont’d
For metastatic breast cancer, numerous active agents exist
Hormonal agents
Chemotherapy agents
Biologic agents
Bisphosphonates
These agents can be combined to optimize treatment.

53. Locally Advanced and Metastatic Breast Cancer
Summary, continued:
Choice of initial therapy depends on
Patient factors: age, comorbidities
Tumour factors: receptor status, Her-2 status
Course of illness: tumour burden, pace of progression
Treatment factors: adjuvant treatment received; response to and tolerance of prior treatment