Breast Cancer and Chemotherapy. Dr.Kensarah Thursday, 20 April 2017

Management of Breast Cancer Neoadjuvant Chemotherapy TNM Classification Staging Management of Breast Cancer Neoadjuvant Chemotherapy Adjuvant Chemotherapy Thursday, 20 April 2017

TNM classification Primary tumor (T) : TX: Primary tumor cannot be assessed. T0: No evidence of primary tumor Tis : DCIS, LCIS, Paget’s disease of the nipple with no tumor . Thursday, 20 April 2017

TNM classification T1: Tumor ≤2.0 cm in greatest dimension T1mic: Microinvasion ≤0.1 cm in greatest dimension T1a: Tumor >0.1 cm but ≤0.5 cm in greatest dimension T1b: Tumor >0.5 cm but ≤1.0 cm in greatest dimension T1c: Tumor >1.0 cm but ≤2.0 cm in greatest dimension Thursday, 20 April 2017

TNM classification T2: Tumor >2.0 cm but ≤5.0 cm in greatest dimension T3: Tumor >5.0 cm in greatest dimension T4: Tumor of any size with direct extension to (a) chest wall or (b) skin. Thursday, 20 April 2017

TNM classification T4a: Extension to chest wall, not including pectoralis muscle. T4b: Edema (including peau d’orange) or ulceration of the skin of the breast. T4c: Both T4a and T4b T4d: Inflammatory carcinoma Thursday, 20 April 2017

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) Thursday, 20 April 2017

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 Thursday, 20 April 2017

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) Thursday, 20 April 2017

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

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% Thursday, 20 April 2017

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 Thursday, 20 April 2017

Management of Breast Cancer II) DCIS : For women with widespread disease ( 2 or more quadrants ) → Mastectomy For women with limited disease → Lumpectomy and Radiation Thursday, 20 April 2017

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 . Thursday, 20 April 2017

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 Thursday, 20 April 2017

Management of Breast Cancer B) Early Invasive Breast Cancer : Adjuvant Chemotherapy is considered for all node positive patients, tumor > 1 cm. Tamoxifen is considered for hormone receptor positive patients with cancer > 1 cm Thursday, 20 April 2017

Management of Breast Cancer C) Advanced Regional Breast Cancer : Operable stage III A : MRM followed by adjuvant chemotherapy, followed by adjuvant radiotherapy. Thursday, 20 April 2017

Management of Breast Cancer 2.inoperable stage III a and stage III b : Neoadjuvant chemotherapy MRM , followed by adjuvant chemotherapy, followed by adjuvant radiotherapy. Thursday, 20 April 2017

Management of Breast Cancer D) Distant metastases: Treatment for stage IV breast cancer is not curative Goal: prolong survival and enhance a women’s quality of life. Hormonal therapy preferred versus chemotherapy. Thursday, 20 April 2017

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 Thursday, 20 April 2017

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. Thursday, 20 April 2017

Neoadjuvant Chemotherapy Consistently, patients treated with neoadjuvant chemotherapy were more likely to be treated with breast conservation. Thursday, 20 April 2017

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. Thursday, 20 April 2017

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. Thursday, 20 April 2017

Neoadjuvant Chemotherapy If histology demonstrates a localized tumor with negative margins, radiation can commence and the breast preserved. Thursday, 20 April 2017

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. Thursday, 20 April 2017

Neoadjuvant Chemotherapy For a diffuse tumor with many satellite foci and positive margins, mastectomy maybe required. Thursday, 20 April 2017

Neoadjuvant Chemotherapy for Operable Breast Cancer Neoadjuvant therapy can achieve high response rates and may permit conservative surgery in more advanced breast cancer. Thursday, 20 April 2017

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 Thursday, 20 April 2017

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 . Thursday, 20 April 2017

Neoadjuvant Chemotherapy for Operable Breast Cancer For these and other concerns, investigators have treated earlier stage patients with preoperative chemotherapy. Thursday, 20 April 2017

Neoadjuvant Chemotherapy “Success of neoadjuvant chemotherapy in conversion of mastectomy to breast conservation surgery.” Harbor-UCLA Medical Center, Torrance, California, USA , Am Surg. 2006 Oct;72(10):935-8 Thursday, 20 April 2017

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 Oct;72(10):935-8 Thursday, 20 April 2017

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 Oct;72(10):935-8 Thursday, 20 April 2017

Neoadjuvant Chemotherapy Mean tumor size was 51 mm. 62 % were larger than 4 cm. Harbor-UCLA Medical Center, Torrance, California, USA , Am Surg. 2006 Oct;72(10):935-8 Thursday, 20 April 2017

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 Oct;72(10):935-8 Thursday, 20 April 2017

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 Oct;72(10):935-8 Thursday, 20 April 2017

Neoadjuvant Chemotherapy “Axillary lymph node count is lower after neoadjuvant chemotherapy” PMID: 16720159 [PubMed - indexed for MEDLINE]. Am J Surg. 2006 Jun;191(6):830-1. Thursday, 20 April 2017

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 Jun;191(6):830-1. Thursday, 20 April 2017

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 Jun;191(6):830-1. Thursday, 20 April 2017

Neoadjuvant Chemotherapy CONCLUSION: A low lymph node count is more common in patients after treatment with neoadjuvant chemotherapy. Thursday, 20 April 2017

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-Apr;4(2):125-31. Thursday, 20 April 2017

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-Apr;4(2):125-31. Thursday, 20 April 2017

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-Apr;4(2):125-31. Thursday, 20 April 2017

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-Apr;4(2):125-31. Thursday, 20 April 2017

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-Apr;4(2):125-31. Thursday, 20 April 2017

Pathological Response after neoadjuvant chemo 112 patients (82%) presented minimal pathological response of the primary tumor. Cancer J Sci Am. 1998 Mar-Apr;4(2):125-31. Thursday, 20 April 2017

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-Apr;4(2):125-31. Thursday, 20 April 2017

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-Apr;4(2):125-31. Thursday, 20 April 2017

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-Apr;4(2):125-31. Thursday, 20 April 2017

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 Thursday, 20 April 2017

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. Thursday, 20 April 2017

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. Thursday, 20 April 2017

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. Thursday, 20 April 2017

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) Thursday, 20 April 2017

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 % Thursday, 20 April 2017

Meta- Analysis of Adjuvant Chemotherapy for Breast Cancer Absolute benefits appear greater for node-positive patients than for node-negative patients. Thursday, 20 April 2017

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. Thursday, 20 April 2017

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 Thursday, 20 April 2017

Meta- Analysis of Adjuvant Chemotherapy for Breast Cancer In summary: Is thought to be proportionately similar in node-positive and node-negative patients. Thursday, 20 April 2017

Meta- Analysis of Adjuvant Chemotherapy for Breast Cancer The rule of constant proportional benefit is not entirely true. Thursday, 20 April 2017

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. Thursday, 20 April 2017

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% Thursday, 20 April 2017

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% Thursday, 20 April 2017

Meta- Analysis of Adjuvant Chemotherapy for Breast Cancer Women older than 70 years did not appear to benefit from the addition of adjuvant polychemotherapy. Thursday, 20 April 2017

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 Thursday, 20 April 2017

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. Thursday, 20 April 2017

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. Thursday, 20 April 2017

Newer approaches in chemotherapy for Breast Cancer This has led to the hypothesis that Dose intensity of chemotherapy is important in patient outcome. Thursday, 20 April 2017

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 Thursday, 20 April 2017

New Agents: Taxanes The taxanes are a group of drugs that includes : 1. Paclitaxel (Taxol) 2. Docetaxel (Taxotere Taxanes : Antimitotic Agent. Thursday, 20 April 2017

New Agents:Taxanes 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 Thursday, 20 April 2017

New Agents:Taxanes 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 Thursday, 20 April 2017

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. Thursday, 20 April 2017

New Agents: Taxanes Taxanes stop the microtubules from breaking down; cancer cells become so clogged with microtubules that they cannot grow and divide. Thursday, 20 April 2017

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 Thursday, 20 April 2017

Cell cycle Thursday, 20 April 2017

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 (doxorubicin–cyclophosphamide) as postoperative adjuvant therapy of lymph node-positive breast cancer in 3170 women Thursday, 20 April 2017

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 1998;17:101a. Thursday, 20 April 2017

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. Thursday, 20 April 2017

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. Thursday, 20 April 2017

New agents : Trastuzumab Trastuzumab ( Herceptin) is a humanized murine monoclonal antibody raised against the erbB-2 or HER2 surface receptor. Thursday, 20 April 2017

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. Thursday, 20 April 2017

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+ Thursday, 20 April 2017

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. Thursday, 20 April 2017

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. Thursday, 20 April 2017

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. Thursday, 20 April 2017

New agents : Trastuzumab In the adjuvant setting, large, randomised trials demonstrate improved outcome for trastuzumab with chemotherapy followed by a year of trastuzumab. Thursday, 20 April 2017

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. Thursday, 20 April 2017

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. Thursday, 20 April 2017

New agents : Trastuzumab 3. Very expensive. Approx. Price: $3047.21 per 1Each GENENTECH, INC. Thursday, 20 April 2017

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 14-20;365(9472):1687-717 Thursday, 20 April 2017

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) Thursday, 20 April 2017

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 Thursday, 20 April 2017

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. Thursday, 20 April 2017

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%. Thursday, 20 April 2017

Early Breast Cancer Trialists' Collaborative Group (EBCTCG) 5 years are significantly more effective than just 1-2 years of tamoxifen Thursday, 20 April 2017

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 Thursday, 20 April 2017

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 Thursday, 20 April 2017

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. Thursday, 20 April 2017

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 Thursday, 20 April 2017

Preoperative Vs Post operative chemotherapy Results: total of 241 patients underwent BCT, 268 patients underwent mastectomy. Among BCT patients who had initial tumor size >2.0 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). Thursday, 20 April 2017

Preoperative Vs Post operative chemotherapy The re-excision rate and total number of breast operations did not significantly differ between the groups. Thursday, 20 April 2017

Preoperative Vs Post operative chemotherapy Among BCT patients who had initial tumor size <=2 cm, preoperative chemotherapy had no impact on volume of breast tissue excised, re-excision rate, or number of breast operations (P > 0.05). Thursday, 20 April 2017