Breast Cancer and Chemotherapy.

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Breast Cancer and Chemotherapy.

• Dr.Kensarah

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• TNM Classification
• Staging
• Management of Breast Cancer
• Neoadjuvant Chemotherapy
• Adjuvant Chemotherapy

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TNM classification

• Primary tumor (T)
• TX Primary tumor cannot be assessed.
• T0 No evidence of primary tumor
• Tis DCIS, LCIS, Pagets disease of the nipple
  with no tumor .

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TNM classification

• T1 Tumor 2.0 cm in greatest dimension
• T1mic Microinvasion 0.1 cm in greatest
  dimension
• T1a Tumor gt0.1 cm but 0.5 cm in greatest
  dimension
• T1b Tumor gt0.5 cm but 1.0 cm in greatest
  dimension
• T1c Tumor gt1.0 cm but 2.0 cm in greatest
  dimension

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TNM classification

• T2 Tumor gt2.0 cm but 5.0 cm in greatest
  dimension
• T3 Tumor gt5.0 cm in greatest dimension
• T4 Tumor of any size with direct extension to
  (a) chest wall or (b) skin.

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TNM classification

• T4a Extension to chest wall, not including
  pectoralis muscle.
• T4b Edema (including peau dorange) or
  ulceration of the skin of the breast.
• T4c Both T4a and T4b
• T4d Inflammatory carcinoma

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TNM classification

• Regional lymph nodes (N)
• NX Regional lymph nodes cannot be assessed
  (e.g., previously removed)
• N0 No regional lymph node metastasis
• N1 Metastasis to movable ipsilateral axillary
  lymph node(s)

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TNM classification

• N2 Metastasis to ipsilateral axillary lymph
  node(s) fixed or matted, or in clinically
  apparent ipsilateral internal mammary nodes in
  the absence of clinically evident lymph node
  metastasis

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TNM classification

• N3-
• N3a Metastasis in ipsilateral infraclavicular
  lymph node(s)
• N3b Metastasis in ipsilateral internal mammary
  lymph node(s) and axillary lymph node(s)
• N3c Metastasis in ipsilateral supraclavicular
  lymph node(s)

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Staging of Breast Cancer
Stage Tumor Size L.N involvement Metastasis
I lt 2 cm No No
II 2-5 cm No or in same side of breast No
III gt 5 cm Yes on same side of breast No
IV Yes
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Management of Breast Cancer

• A) In situ Breast Cancer
• I ) LCIS
• Observation with or w/o Tamoxifen
• The goal of treatment is to prevent or detect
  cancer in early stages, which might develop in
  25-35

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Management of Breast Cancer

• There is no benefit to excising LCIS, as the
  disease diffusely involves both breasts and the
  risk of invasive cancer is equal for both breasts

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Management of Breast Cancer

• II) DCIS
• For women with widespread disease ( 2 or more
  quadrants ) ? Mastectomy
• For women with limited disease ? Lumpectomy and
  Radiation

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Management of Breast Cancer

• B) Early Invasive Breast Cancer
• Includes stage I,IIa , or IIb
• Mastectomy or Lumpectomy and radiation therapy
• Axillary Lymph node dissection .

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Management of Breast Cancer

• Relative Contraindication to breast conservation
  therapy
• Prior radiation therapy to the breast or chest
  wall.
• Positive surgical margins.
• Multicentric disease
• Scleroderma

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Management of Breast Cancer

• B) Early Invasive Breast Cancer
• Adjuvant Chemotherapy is considered for all node
  positive patients, tumor gt 1 cm.
• Tamoxifen is considered for hormone receptor
  positive patients with cancer gt 1 cm

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Management of Breast Cancer

• C) Advanced Regional Breast Cancer
• Operable stage III A
• MRM followed by adjuvant chemotherapy, followed
  by adjuvant radiotherapy.

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Management of Breast Cancer

• 2.inoperable stage III a and stage III b
• Neoadjuvant chemotherapy
• MRM , followed by adjuvant chemotherapy, followed
  by adjuvant radiotherapy.

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Management of Breast Cancer

• D) Distant metastases
• Treatment for stage IV breast cancer is not
  curative
• Goal prolong survival and enhance a womens
  quality of life.
• Hormonal therapy preferred versus chemotherapy.

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Neoadjuvant Chemotherapy

• 7 prospective , randomized trials have evaluated
  the efficacy of chemotherapy administered in the
  neoadjuvant setting prior to breast surgery
  versus administered in the adjuvant setting after
  surgery

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Neoadjuvant Chemotherapy

• Although two of these trials reported improvement
  in disease free survival with the use of
  neoadjuvant chemotherapy, none have demonstrated
  improvement in overall survival.

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Neoadjuvant Chemotherapy

• Consistently, patients treated with neoadjuvant
  chemotherapy were more likely to be treated with
  breast conservation.

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Neoadjuvant Chemotherapy

• From a practical perspective, prior to initiating
  chemotherapy in the neoadjuvant setting, under
  image guidance, a metalic clip is placed into the
  tumor.

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Neoadjuvant Chemotherapy

• IF a complete clinical and radiological tumor
  response occur, preoperative stereotactic wire
  placement alongside the clip will facilitate
  excision of the tumor site.

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Neoadjuvant Chemotherapy

• If histology demonstrates a localized tumor with
  negative margins, radiation can commence and the
  breast preserved.

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Neoadjuvant Chemotherapy

• For a diffuse tumor with satellite lesions,
  consideration of excision prior to radiation
  should be given even if the margins are
  technically cleared.

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Neoadjuvant Chemotherapy

• For a diffuse tumor with many satellite foci and
  positive margins, mastectomy maybe required.

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Neoadjuvant Chemotherapy for Operable Breast
Cancer

• Neoadjuvant therapy can achieve high response
  rates and may permit conservative surgery in more
  advanced breast cancer.

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Neoadjuvant Chemotherapy for Operable Breast
Cancer

• There are reasons to apply to apply this
  treatment to earlier stages of Cancer
• 1st for the lower tumor burdens, the
  probability of drug resistance cells is
  theoretically less.
• Definition Refers to the number of cancer
  cells, the size of a tumor, or the amount of
  cancer in the body Tumor load

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Neoadjuvant Chemotherapy for Operable Breast
Cancer

• 2nd the absolute number of tumor cells left
  after treating a small tumor burden may be below
  a threshold, above which re-growth will
  occur.ie, no recurrence .

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Neoadjuvant Chemotherapy for Operable Breast
Cancer

• For these and other concerns, investigators have
  treated earlier stage patients with preoperative
  chemotherapy.

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Neoadjuvant Chemotherapy

• Success of neoadjuvant chemotherapy in
  conversion of mastectomy to breast conservation
  surgery.
• Harbor-UCLA Medical Center, Torrance, California,
  USA , Am Surg. 2006 Oct72(10)935-8

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Neoadjuvant Chemotherapy

• Objective to determine the success of
  Neoadjuvant Chemotherapy in achieving Breast
  conservation in women who initially were not
  candidates for BC.
• Harbor-UCLA Medical Center, Torrance,
  California, USA , Am Surg. 2006 Oct72(10)935-8

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Neoadjuvant Chemotherapy

• Tumors were predominantly infiltrating ductal
  carcinoma (83.3 )
• high grade (62.2 )
• Chemo Cyclophosphamide, Doxorubicin and 5 FU.
• Harbor-UCLA Medical Center, Torrance, California,
  USA , Am Surg. 2006 Oct72(10)935-8

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Neoadjuvant Chemotherapy

• Mean tumor size was 51 mm.
• 62 were larger than 4 cm.
• Harbor-UCLA Medical Center, Torrance, California,
  USA , Am Surg. 2006 Oct72(10)935-8

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Neoadjuvant Chemotherapy

• Results
• Complete clinical response was seen in 32.4
• Complete pathological response was seen in 10.8
• Harbor-UCLA Medical Center, Torrance, California,
  USA , Am Surg. 2006 Oct72(10)935-8

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Neoadjuvant Chemotherapy

• BC was achieved in 56.7 per cent of cases.
• Only initial tumor size predicted tumor
  regression and success of BC . Neither Histology
  nor biological marker.
• Harbor-UCLA Medical Center, Torrance, California,
  USA , Am Surg. 2006 Oct72(10)935-8

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Neoadjuvant Chemotherapy

• Axillary lymph node count is lower after
  neoadjuvant chemotherapy
• PMID 16720159 PubMed - indexed for MEDLINE. Am
  J Surg. 2006 Jun191(6)830-1.

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Neoadjuvant Chemotherapy

• Results
• A total of 143 patients recived NC first.
• 170 patients received surgery first
• PMID 16720159 PubMed - indexed for MEDLINE. Am
  J Surg. 2006 Jun191(6)830-1.

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Neoadjuvant Chemotherapy

• Patients treated with neoadjuvant chemotherapy
  had fewer than 10 L.N retrieved at ALND than
  patients who had the surgery first.
• PMID 16720159 PubMed - indexed for MEDLINE. Am
  J Surg. 2006 Jun191(6)830-1.

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Neoadjuvant Chemotherapy

• CONCLUSION
• A low lymph node count is more common in
  patients after treatment with neoadjuvant
  chemotherapy.

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Pathological Response after neoadjuvant chemo

• Prognostic significance of pathological response
  of primary tumor and metastatic axillary lymph
  nodes after neoadjuvant chemotherapy for locally
  advanced breast carcinoma.
• Cancer J Sci Am. 1998 Mar-Apr4(2)125-31.

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Pathological Response after neoadjuvant chemo

• PATIENTS AND METHODS
• Between January 1989 and April 1995, 148
  consecutive patients with locally advanced breast
  carcinoma participated in the study.
• Cancer J Sci Am. 1998 Mar-Apr4(2)125-31.

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Pathological Response after neoadjuvant chemo

• Of these, 140 patients were treated with three
  courses of 5-fluorouracil, doxorubicin, and
  cyclophosphamide (FAC), followed by modified
  radical mastectomy or definitive radiation
  therapy.
• Cancer J Sci Am. 1998 Mar-Apr4(2)125-31.

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Pathological Response after neoadjuvant chemo

• RESULTS
• Complete response occurred in 11 patients (8)
• Partial response occurred in 88 patients (63).
• No change was recorded in 37 patients (26)
• and progressive disease occurred in 4 patients
  (3)
• Cancer J Sci Am. 1998 Mar-Apr4(2)125-31.

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Pathological Response after neoadjuvant chemo

• Maximal pathological response of the primary
  tumor (in situ carcinoma or minimal microscopic
  residual tumor) was observed in 24 (18)
• Cancer J Sci Am. 1998 Mar-Apr4(2)125-31.

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Pathological Response after neoadjuvant chemo

• 112 patients (82) presented minimal pathological
  response of the primary tumor.
• Cancer J Sci Am. 1998 Mar-Apr4(2)125-31.

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Pathological Response after neoadjuvant chemo

• A significant correlation was noted between
  pathological response of primary tumor and the
  number of metastatic axillary lymph nodes
• Cancer J Sci Am. 1998 Mar-Apr4(2)125-31.

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Pathological Response after neoadjuvant chemo

• CONCLUSION
• After neoadjuvant chemotherapy, pathological
  responses of both primary tumor and metastatic
  axillary lymph nodes had a marked prognostic
  significance and influenced outcome for patients
  with locally advanced breast carcinoma.
• Cancer J Sci Am. 1998 Mar-Apr4(2)125-31.

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Pathological Response after neoadjuvant chemo

• The results suggest that maximal tumor shrinkage
  of potentially involved axillary nodes may
  represent a major goal of neoadjuvant
  chemotherapy
• Cancer J Sci Am. 1998 Mar-Apr4(2)125-31.

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Adjuvant Chemotherapy for Operable Breast Cancer

• The first trials of prolonged postoperative
  chemotherapy in operable breast cancer were
  started by the National Surgical Adjuvant Breast
  and Bowel Project (NSABP) in 1972 and by the
  NCI National Cancer institue of Italy in 1973

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Adjuvant Chemotherapy for Operable Breast Cancer

• The results from these two trials are similar and
  convincingly positive for women undergoing
  chemotherapy who are younger than 50 years of
  age.

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Adjuvant Chemotherapy for Operable Breast Cancer

• In contrast to the positive effect of
  chemotherapy in younger patients, women older
  than 50 years of age did not significantly
  benefit from the use of adjuvant cytotoxic
  chemotherapy.

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• In respect to adjuvant chemotherapy,
  information from more than 30,000 women in 69
  trials was collected.

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• These patients were involved in randomization
  between
• polychemotherapy Vs no treatment (18,000)
• longer Vs shorter polychemotherapy (6000)
• anthracyclin containing regimens Vs CMF ( 6000)

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• Overall, the results showed that patients who
  received treatment had a proportional reduction
  in the recurrence of 23.5 and a proportional
  reduction in death of 15.3

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• Absolute benefits appear greater for
  node-positive patients than for node-negative
  patients.

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• However, the reduction in annual odds of
  recurrence is similar.
• 28 for node-negative patients
• 33 for node-positive women.

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• In summary
• adjuvant chemotherapy with multiple drugs
  produces a statistically significant reduction in
  the odds of breast cancer recurrence or death

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• In summary
• Is thought to be proportionately similar in
  node-positive and node-negative patients.

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• The rule of constant proportional benefit is not
  entirely true.

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• The benefits of adjuvant polychemotherapy
  appeared to be greatest in younger women, with an
  inverse relationship of benefit to age.

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• For women younger than 40, polychemotherapy
  reduced the odds of recurrence by 37 and death
  by 28

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• This benefit tended to decline in older women.
• However, even for women aged 60 69 when
  randomized, chemotherapy reduced the proportion
  with recurrence by 18 and the proportion dying
  by 9

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• Women older than 70 years did not appear to
  benefit from the addition of adjuvant
  polychemotherapy.

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Meta- Analysis of Adjuvant Chemotherapy for
Breast Cancer

• A small advantage of anthracycline- containing
  regimens was also seen in this large analysis
• Anthracyclines such as doxorubicin and
  epirubicin

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Newer approaches in chemotherapy for Breast Cancer

• Dose intensity
• In the analysis of the Milan CMF trial, the
  question of chemotherapy dose was investigated as
  a determination of effectiveness.

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Newer approaches in chemotherapy for Breast Cancer

• The outcome of patients receiving more than 85
  of their calculated chemotherapy dose was
  significantly better than for patients who
  received less than 65 of their scheduled dose.

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Newer approaches in chemotherapy for Breast Cancer

• This has led to the hypothesis that
• Dose intensity of chemotherapy is important in
  patient outcome.

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New agents

• Addition of the novel class of drugs, the
  taxanes, to the doxorubicin-containing regimens
  in CALGB resulted in an improved disease free and
  overall survival outlook.
• Journal of the National Cancer Institute
  Monographs, No. 30, 88-95, 2001
• CALGB Cancer And Leukemia Group B

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New Agents Taxanes

• The taxanes are a group of drugs that includes
• 1. Paclitaxel (Taxol)
• 2. Docetaxel (Taxotere
• Taxanes Antimitotic Agent.

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New AgentsTaxanes

• Paclitaxel and docetaxel undoubtedly represent
  the most active chemotherapeutic agents developed
  in the last decade for the treatment of advanced
  breast cancer
• Journal of the National Cancer Institute
  Monographs, No. 30, 88-95, 2001

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New AgentsTaxanes

• Outstanding features of these agents includes
• first, the mechanism of action.
• They affect cell structures called
  microtubules, which play an important role in
  cell functions.
• Journal of the National Cancer Institute
  Monographs, No. 30, 88-95, 2001

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New Agents Taxanes

• In normal cell growth, microtubules are formed
  when a cell starts dividing.
• Once the cell stops dividing, the microtubules
  are broken down or destroyed.

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New Agents Taxanes

• Taxanes stop the microtubules from breaking down
  cancer cells become so clogged with microtubules
  that they cannot grow and divide.

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New Agents Taxanes

• Second
• Their capacity to be combined with almost all
  active chemotherapeutic agents commonly used for
  breast cancer therapy.
• Journal of the National Cancer Institute
  Monographs, No. 30, 88-95, 2001

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• Cell cycle

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New Agents Taxanes

• The large U.S. Intergroup trial, referred to as
  Cancer and Leukemia Group B (CALGB) 9344,
  explored the value of adding four cycles of
  paclitaxel to four cycles of AC
  (doxorubicincyclophosphamide) as postoperative
  adjuvant therapy of lymph node-positive breast
  cancer in 3170 women

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New Agents Taxanes

• The superior results of the paclitaxel arm were
  reported at its first planned interim analysis,
  conducted at a median follow-up time of 20
  months, and were presented at the 1998 meeting of
  the American Society of Clinical Oncology (ASCO)
  
• Henderson IC, et al. Improved disease-free
  and overall survival from the addition of
  sequential paclitaxel but not from the escalation
  of doxorubicin dose level in the adjuvant
  chemotherapy of patients with node-positive
  primary breast cancer abstract. Proc ASCO
  199817101a.

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New Agents Taxanes

• an update with a median follow-up of 30 months
  was presented to the ODAC (Oncology Drug Advisory
  Committee) with subsequent registration of the
  paclitaxel-based adjuvant regimen for lymph
  node-positive disease by the FDA in late 1999.

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New Agents Taxanes

• Side effects of Taxanes
• 1.Nausea and vomiting
• 2.Bone Marrow suppression
• 3.Hypersensitivity Recation
• 4.Joint and muscle pain.
• 5.Loss of hair.

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New agents Trastuzumab

• Trastuzumab ( Herceptin) is a humanized murine
  monoclonal antibody raised against the erbB-2 or
  HER2 surface receptor.

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New agents Trastuzumab

• This receptor related to erbB-1 or the epidermal
  growth factor receptor (EGFr), is the target gene
  amplification and high level overexpression in
  about 20 of patients of human breast cancer.

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New agents Trastuzumab

• Overexpression of the protein product of the
  erbB-2 gene is measured by immunohistochemistry
  and usually quantitatively expressed from zero to
  3

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New agents Trastuzumab

• Gene amplification is measured by the fluorescent
  in Situ hybridization (FISH).
• Those cancers with 3 expression or amplification
  by FISH may respond to trastuzumab.

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New agents Trastuzumab

• Her2/neu activation initiates signalling cascades
  that result in proliferation, angiogenesis and
  survival of breast cancer cells.
• Trastuzumab is a monoclonal antibody against
  Her2.
• Fox Chase Cancer Center, Division of Medical
  Sciences, Department of Medical Oncology, 333
  Cottman Ave, Philadelphia, PA 19111, USA.

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New agents Trastuzumab

• When trastuzumab is used preoperatively,
  apoptosis is seen in resected tumours.
• Fox Chase Cancer Center, Division of Medical
  Sciences, Department of Medical Oncology, 333
  Cottman Ave, Philadelphia, PA 19111, USA.

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New agents Trastuzumab

• In the adjuvant setting, large, randomised trials
  demonstrate improved outcome for trastuzumab with
  chemotherapy followed by a year of trastuzumab.

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New agents Trastuzumab

• In fact, addition of trastuzumab to conventional
  chemotherapy has improved survival in metastatic
  breast cancer patients, and some patients have
  experienced dramatic regression of cancer.

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New agents Trastuzumab

• Limitation to this approach are
• 1.relatively small number of patients with
  HER2-positive tumors
• 2. The addidative adverse effects of trastuzumab
  and anthracyclines on cardiac function.

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New agents Trastuzumab

• 3. Very expensive.
• Approx. Price 3047.21 per 1Each
• GENENTECH, INC.

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Early Breast Cancer Trialists' Collaborative
Group (EBCTCG)

• Effects of chemotherapy and hormonal therapy for
  early breast cancer on recurrence and 15-year
  survival an overview of the randomised trials.
• Lancet. 2005 May 14-20365(9472)1687-717

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Early Breast Cancer Trialists' Collaborative
Group (EBCTCG)

• randomised trials in early breast cancer have
  assessed the 5 year and 10-year effects of
  various systemic adjuvant therapies on breast
  cancer recurrence and survival (1985-2000)

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Early Breast Cancer Trialists' Collaborative
Group (EBCTCG)

• FINDINGS
• Allocation to about 6 months of
  anthracycline-based polychemotherapy (eg, with
  FAC) reduced the annual breast cancer death rate
  by about 38 for women younger than 50 years

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Early Breast Cancer Trialists' Collaborative
Group (EBCTCG)

• The Annual breast cancer death rate reduced by
  about 20 for those of age 50-69 years , largely
  irrespective of the use of tamoxifen and of
  oestrogen receptor (ER) status, nodal status, or
  other tumour characteristics.

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Early Breast Cancer Trialists' Collaborative
Group (EBCTCG)

• For ER-positive disease only, allocation to about
  5 years of adjuvant Tamoxifen reduces the annual
  breast cancer death rate by 31.

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Early Breast Cancer Trialists' Collaborative
Group (EBCTCG)

• 5 years are significantly more effective than
  just 1-2 years of tamoxifen

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Early Breast Cancer Trialists' Collaborative
Group (EBCTCG)

• For middle-aged women with ER-positive disease
  (the commonest type of breast cancer), the breast
  cancer mortality rate was decreased by 50
  throughout the next 15 years after 6 months of
  anthracycline-based chemotherapy (with a
  combination such as FAC ) followed by 5 years of
  adjuvant tamoxifen

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Preoperative Vs Post operative chemotherapy

• Impact of Preoperative Versus Postoperative
  Chemotherapy on the Extent and Number of Surgical
  Procedures in Patients Treated in Randomized
  Clinical Trials for Breast Cancer

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Preoperative Vs Post operative chemotherapy

• Methods
• The records of 509 consecutive patients with
  T1-T3, N0-N2 breast cancer who were treated in
  prospective randomized clinical trials of
  chemotherapy between 1998 and 2005.

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Preoperative Vs Post operative chemotherapy

• Analysis included
• The final surgical procedure (BCT or mastectomy),
• The number of operations
• In patients who underwent BCT, re-excision
  rates,
• the total volume of breast tissue excised

102
Preoperative Vs Post operative chemotherapy

• Results
• total of 241 patients underwent BCT,
• 268 patients underwent mastectomy.
• Among BCT patients who had initial tumor size
  gt2.0 cm, patients who received preoperative
  chemotherapy had significantly smaller volumes of
  breast tissue excised compared with patients who
  received postoperative chemotherapy (113 cm3 vs.
  213 cm3, P 0.004).

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Preoperative Vs Post operative chemotherapy

• The re-excision rate and total number of breast
  operations did not significantly differ between
  the groups.

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Preoperative Vs Post operative chemotherapy

• Among BCT patients who had initial tumor size lt2
  cm, preoperative chemotherapy had no impact on
  volume of breast tissue excised, re-excision
  rate, or number of breast operations (P gt 0.05).