breast%20cancer
BREAST CANCER
Breast cancer is the presence of malignant breast nodule, mass or abscess.
Most common symptom of breast cancer is a new lump or mass in the breast. The lump or mass is usually painless, hard & irregular but it can also be tender, soft, rounded or painful.
Other signs & symptoms include breast pain or nipple pain, nipple discharge, nipple retraction and presence of breast skin changes (eg peau d' orange, nipple excoriation, scaling, inflammation, skin tethering, ulceration, abscess).

Principles of Therapy

Preoperative Chemotherapy

  • All chemotherapy administration before surgery is preferred
    • Modalities used in adjuvant therapy may also be used eg endocrine and targeted therapy
  • Purpose is to reduce tumor size which allows complete removal of the tumor with less extensive surgery
  • Can predict how the cancer cells respond to chemotherapeutic drugs
  • Considered in women with large clinical stage IIA, IIB, and T3N1M0 tumors who meet the criteria for breast-conserving therapy except for tumor size and those who wish to undergo breast-conserving therapy
  • Indications:
    • Tumor size >2 cm (T2, T3)
    • Cancer does not involve the surrounding skin or chest wall
    • LN enlarged but movable
  • Endocrine therapy alone, ie Tamoxifen or aromatase inhibitor (for postmenopausal women; administered with ovarian suppression to premenopausal women) may be given in hormone receptor-positive disease
  • Patients with HER2-positive tumors should be treated with pre-operative chemotherapy incorporating Trastuzumab for at least 9 weeks

Pharmacotherapy

Risk Reduction for Carcinoma In Situ

Tamoxifen

  • Competitively binds to cytoplasmic ER in breast, uterus, vagina, anterior pituitary and tumors containing high levels of ER
    • Competitive binding protects against development of breast cancer
  • Decreases breast cancer risk in healthy premenopausal and postmenopausal women ≥35 years old
  • More effective risk reduction agent for most menopausal women who want a non-surgical risk reduction therapy but has more toxic effects
  • May be considered as an adjuvant therapy in DCIS patients who underwent breast conservation therapy especially in ER-positive DCIS; benefit of Tamoxifen in ER-negative DCIS is uncertain
    • Reduces the risk of cancer recurrence on the ipsilateral breast
  • May be considered as risk reduction therapy in DCIS patients treated with mastectomy
    • Reduces the development of contralateral 2nd primary breast carcinoma
  • Studies have shown that Tamoxifen can reduce the risk of invasive breast cancer in premenopausal and postmenopausal patients
    • Used in ER-positive tumor
    • Aromatase inhibitor may be of advantage in postmenopausal patients <60 year old or with thromboembolism problems
  • Advised to be taken for 5 years

Raloxifene

  • Long-term use was shown to be less effective but a safer risk reduction agent compared to Tamoxifen in postmenopausal women

Surgery

  • Preventive bilateral mastectomy may be an alternative for patients at high risk of developing invasive breast cancer

Chemotherapeutic Agents for Invasive Breast Cancer

  • Several combination treatment regimens are used for adjuvant chemotherapy
    • Usually includes 4-8 cycles of taxane- and/or anthracycline-based regimen
  • Chemotherapy response depends on ER status
  • Platinum compounds may be given to BRCA1 patients; cells deficient of BRCA1 are hypersensitive to platinum compounds

Trastuzumab

  • Indicated for patients who are HER2 positive with (nonresponsive, incompletely or highly) endocrine-responsive tumors and low, intermediate or high-risk categories to decrease disease recurrence
    • Indicated for patients with early breast cancer who are HER2 positive, given after surgery, adjuvant or neoadjuvant chemotherapy, and radiotherapy (if applicable)
  • Can help slow cancer growth and may also stimulate the immune system to more effectively fight the cells
    • Reduces risk of recurrence by half and improves survival
  • Given to both premenopausal and postmenopausal patients
  • May be given concurrently with a taxane following anthracycline or after completion of all chemotherapy
  • One year is the accepted standard treatment duration
  • Contraindicated in patients with low left ventricular ejection fraction (<50%)

Non-Trastuzumab Combinations (HER2-Negative Disease)

Preferred Adjuvant Regimens:

  • Dose-dense Doxorubicin, Cyclophosphamide (AC) followed by Paclitaxel (T) every 2 weeks
  • Dose-dense Doxorubicin, Cyclophosphamide (AC) followed by Paclitaxel every week
  • Docetaxel, Cyclophosphamide (TC)

Conditional Regimens:

  • Cyclophosphamide, Methotrexate, Fluorouracil (CMF) 
  • Dose-dense Doxorubicin, Cyclophosphamide (AC)
  • Doxorubicin, Cyclophosphamide (AC) every 3 weeks
  • Doxorubicin, Cyclophosphamide (AC) followed by Paclitaxel every week

Other Recommended Regimens:

  • Doxorubicin, Cyclophosphamide (AC) followed by Docetaxel every 3 weeks
  • Epirubicin, Cyclophosphamide (EC)
  • Docetaxel, Doxorubicin, Cyclophosphamide (TAC)

Trastuzumab Combinations (HER2-Positive Disease)

Preferred Adjuvant Regimens:

  • Doxorubicin, Cyclophosphamide (AC) followed by Paclitaxel (T) plus Trastuzumab with or without Pertuzumab
  • Docetaxel, Carboplatin, Trastuzumab (TCH) with or without Pertuzumab
  • Paclitaxel plus Trastuzumab

Conditional Regimens:

  • Docetaxel plus Cyclophosphamide plus Trastuzumab

Other Adjuvant Regimens:

  • Doxorubicin, Cyclophosphamide (AC) followed by Docetaxel plus Trastuzumab with or without Pertuzumab
Adjuvant Endocrine Therapy
  • Offered to patients with detectable expression of HR (>1% invasive cancer cells)
  • Minimum duration of therapy is 5 years but recent data suggest that extending therapy for an additional 5 years reduces risk recurrence and improves disease-free survival
    • Discussion should be made with the patient regarding the benefits and risks of extended therapy
  • Sequential administration of hormone therapy after chemotherapy is recommended for patients w/ high-risk features (eg lymph node metastasis, unknown recurrence score, intermediate to high recurrence score)

Recommended Adjuvant Endocrine Therapy for Premenopausal Women

  • Any of the following:
    • Tamoxifen for 5 years with or without ovarian suppression or
    • Aromatase inhibitor with ovarian suppression for 5 years
  • If patient becomes amenorrheic while on the 5-year Tamoxifen therapy, assessment of FSH, LH & estradiol levels should be done to assure the occurrence of menopause
    • Consider continuing aromatase or Tamoxifen therapy for another 5 years once menopause has been confirmed
  • Continuation of Tamoxifen therapy for up to 10 years should be considered for patients who remain premenopausal 5 years after initiation of adjuvant endocrine therapy

Recommended Adjuvant Endocrine Therapy for Postmenopausal Women

  • Any of the following:
    • Aromatase inhibitor with ovarian suppression for 5 years or
    • Tamoxifen for 2-3 years followed by 1 of the following:
      • Aromatase inhibitor for 2-3 years to complete the 5-year treatment duration or
      • Aromatase inhibitor for 5 years
    • Tamoxifen for 4.5-6 years followed by aromatase inhibitor for 5 years or Tamoxifen therapy for 10 years
      • Monotherapy should only be considered in patients with contraindications to aromatase inhibitor therapy

Aromatase Inhibitors

  • Adjuvant treatment in postmenopausal patients with ER-positive, stages I and II (tumor size <5 cm) invasive carcinoma
  • Based on randomized controlled trials, relative to Tamoxifen, aromatase inhibitors improve clinical outcomes in patients with early ER-positive invasive breast cancer; however, treatment was associated with increased drug costs and slight decrease in follow-up costs compared to Tamoxifen
  • Have the same anti-tumor efficacy and toxicity profiles
  • Anastrozole is recommended for primary adjuvant therapy
  • Exemestane is used as adjuvant therapy following 2-3 years of adjuvant Tamoxifen therapy
  • Letrozole is recommended for primary & extended adjuvant therapy following standard Tamoxifen therapy

Tamoxifen

  • First-line adjuvant endocrine therapy in both pre- & post-menopausal breast cancer patients
Chemotherapy for Recurrent or Metastatic Breast Cancer
  • Consider a taxane- or anthracycline-based regimen
    • Sequential monotherapy rather than concomitant use is recommended
    • Considered as 1st-line agents for patients with HER2-negative metastatic breast cancer who have not yet been on these regimens as adjuvant therapy and for whom treatment with chemotherapy is appropriate
  • Combination of Lapatinib and Capecitabine may be used in patients with HER2-positive tumors who are refractory to therapy with anthracycline, taxane and Trastuzumab
    • Study has shown that the combination was associated with 51% risk reduction of cancer progression
  • No evidence states that combination regimens are superior to sequential single agents
  • HER2-directed therapy, either as a single agent, combined with chemotherapy or with endocrine therapy, should be proposed early to patients with HER2-positive metastatic breast cancer
    • If without contraindications, further anti-HER2 therapy should be considered in patients with HER2-positive metastatic breast cancer who relapsed following adjuvant or any line metastatic anti-HER2 treatment

HER2-Negative Disease

  • Combination regimen composed of sequential single-agent regimens may be used for patients w/ high tumorburden, rapidly progressive disease, & visceral crisis

Preferred Single Agent Regimens

  • Anthracyclines: Doxorubicin, liposomal Doxorubicin
  • Anti-metabolites: Capecitabine, Gemcitabine
  • Microtubule inhibitors: Vinorelbine, Eribulin
  • Taxanes: Paclitaxel
  • PARP inhibitor: Olaparib
    • Treatment option for HER2-negative, germline BRCA 1/2-mutation positive patient

Other Recommended Regimens

  • Cyclophosphamide, Cisplatin, Carboplatin, Docetaxel, albumin-bound Paclitaxel, Epirubicin, Ixabepilone

Conditional Combination Regimens:

  • Doxorubicin, Cyclophosphamide (AC)
  • Epirubicin, Cyclophosphamide (EC)
  • Cyclophosphamide, Methotrexate, Fluorouracil (CMF)
  • Docetaxel and Capecitabine
  • Gemcitabine and Paclitaxel (GT)
  • Gemcitabine and Carboplatin
  • Paclitaxel and Bevacizumab

HER2-Positive Disease
Preferred Regimens

  • Pertuzumab plus Trastuzumab plus Docetaxel
  • Pertuzumab plus Trastuzumab plus Paclitaxel

Other Recommended Regimens

  • Ado-Trastuzumab emtansine (T-DM1)
  • Lapatinib plus Capecitabine
  • Trastuzumab plus Capecitabine
  • Trastuzumab plus Docetaxel
  • Trastuzumab plus Lapatinib (without cytotoxic therapy)
  • Trastuzumab plus Paclitaxel with or without Carboplatin
  • Trastuzumab plus Vinorelbine
  • Trastuzumab plus other agents

Systemic Therapy for Recurrent or Metastatic Disease

HER2-Negative Postmenopausal Patients

Preferred Regimens

  • Abemaciclib plus aromatase inhibitor
  • Abemaciclib plus Fulvestrant
  • Estrogen receptor down-regulator (eg Fulvestrant)
  • Exemestane plus Everolimus
  • Fulvestrant plus Everolimus
  • Non-steroidal aromatase inhibitors (eg Anastrozole, Letrozole)
  • Palbociclib plus aromatase inhibitor
  • Palbociclib plus Fulvestrant
  • Ribociclib plus aromatase inhibitor
  • Ribociclib plus Tamoxifen
  • Serum estrogen receptor modulators (eg Tamoxifen, Toremifene)
  • Steroidal aromatase inactivator (eg Exemestane)
  • Tamoxifen plus Everolimus

Conditional Regimens

  • Abemaciclib
  • Ethinyl estradiol
  • Fluoxymestrone
  • Megestrol acetate 

HER2-Positive Postmenopausal Patients

  • Aromatase inhibitor with or without Trastuzumab
  • Aromatase inhibitor with or without Lapatinib
  • Aromatase inhibitor with or without Lapatinib plus Trastuzumab
  • Fulvestrant with or without Trastuzumab
  • Tamoxifen with or without Trastuzumab

HER2-Targeted Therapy

  • Treatment option for ER/PR-positive, HER2-positive patients
  • Includes any of the following:
    • Pertuzumab plus Trastuzumab plus taxane (preferred regimen)
  • Ado-Trastuzumab emtansine (T-DM1)
    • Trastuzumab plus chemotherapy

Aromatase Inhibitors

  • Used in postmenopausal patients
  • Preferred 1st-line therapy for recurrent disease in postmenopausal women who have received previous antiestrogen therapy and are within 1 year of antiestrogen exposure
  • Used in postmenopausal patients with ER- and/or PR-positive, HER2-negative or positive recurrent or stage IV breast cancer with no prior endocrine therapy within 1 year 

Endocrine Therapy plus Ovarian Ablation or Suppression or Selective ER Modulators

  • Tamoxifen is a standard
  • Used in premenopausal patients with ER- and/or PR-positive, HER2-negative or positive recurrent or stage IV breast cancer with or without prior endocrine therapy within 1 year

CDK4/6 Inhibitors

  • Eg Abemaciclib, Palbociclib, Ribociclib
  • Abemaciclib, Palbociclib, & Ribociclib are highly selective inhibitors of CDK 4/6 kinase activity which are usedto treat hormone receptor-positive, HER2-negative advanced or metastatic breast cancer
  • Palbociclib is given with Letrozole in postmenopausal women as initial endocrine-based therapy or with Fulvestrant in women with disease progression after endocrine therapy
  • Combination therapy of any CDK4/6 inhibitor with an aromatase inhibitor is a preferred regimen for HER2-negative postmenopausal breast cancer patients
  • Ribociclib with Tamoxifen, & Abemaciclib or Palbociclib combined with Fulvestrant are also among the preferred regimens for hormone receptor-positive, HER2-negative postmenopausal breast cancer patients

Monoclonal Antibody Therapy
Bevacizumab

  • May be used to treat metastatic breast cancer which is commonly used in combination with Paclitaxel
  • Prevents angiogenesis

Pertuzumab

  • A human epidermal growth factor receptor (HER) dimerisation inhibitor preventing HER2 heterodimerisation with other HER receptors thereby inhibiting HER signalling pathway activation
  • Used in combination with Trastuzumab, a taxane, chemotherapeutic agents & HER2-targeted therapy in the treatment of HER2-positive premenopausal or postmenopausal patients with recurrent or metastatic disease, regardless if with history of endocrine therapy in the past 12 months
    • Also used for the treatment of locally advanced, inflammatory or early stage HER2-positive breast cancer
  • LVEF assessment should be done at baseline and during treatment; discontinue if with confirmed clinically significant decline in LV function

Trastuzumab

  • Indicated for high-risk, HER2-positive tumor
    • Added in pre-op chemotherapy regimens in patients with HER2-positive tumors
  • May be used to treat metastatic breast cancer, with or without chemotherapy
    • May be given as monotherapy to patients with HER2-overexpressing tumors who have received at least 2 regimens of chemotherapy for metastatic disease
  • May be used as adjuvant therapy along with chemotherapy in cancer recurrence risk reduction and as neoadjuvant therapy with chemotherapy to reduce the tumor size prior to surgical operation
  • Combination with an anthracycline is related to significant cardiac toxicity, except as part of the neoadjuvant Trastuzumab with Paclitaxel followed by CEF regimen

Selective ER Down-Regulator

  • Eg Fulvestrant
  • Recommended regimen for postmenopausal, HER2-negative patients with recurrent or metastatic breast cancer when given in combination with Palbociclib, Abemaciclib, or Everolimus
  • May also be considered in postmenopausal, HER2-positive patients with recurrent or metastatic breast cancer
    • Given with or without Trastuzumab

Selective ER Modulators

  • Eg Tamoxifen, Toremifene
  • Preferred regimen for postmenopausal, HER2-negative patients with recurrent or metastatic breast cancer
  • Tamoxifen with or without Trastuzumab is an alternative option for postmenopausal, HER2-positive patients with recurrent or metastatic disease

Other Agents

Bisphosphonates and Denosumab

  • Given in addition to endocrine therapy or chemotherapy if bone metastasis is present
  • Ibandronic acid, Pamidronate or Zoledronic acid (with calcium citrate and vit D)
    • Help strengthen bones and decrease the risk of fractures and bone pains
  • Zoledronic acid may be more effective than Pamidronic acid in lytic breast metastasis
  • A randomized trial had shown Denosumab to have slightly better tolerability and efficacy when compared to Zoledronic acid

Mammalian Target of Rapamycin (mTOR) Pathway Inhibitor

  • Inhibits protein in cells that promotes growth and division
  • Eg Everolimus
    • Used in addition to Exemestane, Fulvestrant, or Tamoxifen in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer that had progressed or recurred during treatment with a non-steroidal aromatase inhibitor
    •  Can also be combined with Tamoxifen
    • May also stop angiogenesis which can help limit tumor growth
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