Neoadjuvant Chemotherapy of Breast Cancer

1
Neoadjuvant Chemotherapy of Breast Cancer

• Grand Rounds
• March 2, 2007
• Coy Heldermon

2
Case

• 37yo AAF finds a lump in her right breast in Nov.
  
• Biopsy Jan 2007 - ER-/PR-/HER-2 na, grade III
  Inv. Ductal Ca. 2/2 nodes involved.
• PMH asthma and BTL
• SH divorced mother of 3 teenagers, bus driver,
  No TEDS
• FH maternal aunt and great aunt with breast
  cancer in their 50s

3
Imaging

• CT CAP
• 4.0 x 3.3 mass within the right breast.
• right axillary lymph node measuring 2.9 x 1.7 cm.
  
• a small subpectoral lymph node
• bulky bilateral internal mammary lymphadenopathy.
  right internal mammary lymph node measures 2.5 x
  1.6 cm
• Small prevascular and right cardiophrenic angle
  lymph nodes are noted. Right paratracheal lymph
  nodes are at the upper limits of normal size.
• Small bilateral pleural effusions are present.
• Bone scan negative MUGA EF 65

4
PE and Labs

• Exam only remarkable for R breast with subareolar
  mass of 10.5 x 12.5 cm and sites of core biopsy
  and SLN dissection appreciated.
• Abnormal labs Hgb 11.9, albumin 3.4, CA125 32
  (CEA, CA15-3 and HCG not elevated)
• By imaging T2N3b(ish), by exam T3 either way
  stage approximately IIIc
• Patient was offered neoadjuvant dose dense ACgtT.

5
(No Transcript)
6
Effect of Preoperative Chemotherapy on
Local-Regional Disease in Women With Operable
Breast Cancer Findings From National Surgical
Adjuvant Breast and Bowel Project B-18By Bernard
Fisher, Ann Brown, Eleftherios Mamounas, Samuel
Wieand, Andre Robidoux, Richard G. Margolese,
Anatolia B. Cruz, Jr, Edwin R. Fisher, D.
Lawrence Wickerham, Norman Wolmark, Arthur
DeCillis, James L. Hoehn,Alan W. Lees, and
Nikolay V. DimitrovJ Clin Oncol 152483-2493.AC
x 4 pre vs post surgery
Not all tumors are created equal. Smaller tumors
are more likely to reach CR. DUH!
7
NSABP B18
Lumpectomy odds are improved with neoadjuvant
therapy.
8
A reduction in the requirements for mastectomy in
a randomized trial ofneoadjuvant chemoendocrine
therapy in primary breast cancerA. Makris, T. J.
Powles, S. E. Ashley, J. Chang, T. Hickish, V.
A.Tidy, A. G. Nash H. T. FordAnnals of
Oncology 9 1179-1184, 1998.mitozantrone,
methotrexate, mitomycin C, tamoxifen
Neoadjuvant therapy increases the chances of
lumpectomy
9
Without adversely affecting prognosis
10
NSABP B27
Effect of Preoperative Chemotherapy on the
Outcome of Women With Operable Breast Cancer By
Bernard Fisher, John Bryant, Norman Wolmark,
Eleftherios Mamounas, Ann Brown, Edwin R.
Fisher, D. Lawrence Wickerham, Mirsada Begovic,
Arthur DeCillis, Andre Robidoux, Richard G.
Margolese, Anatolio B. Cruz, Jr, James L. Hoehn,
Alan W. Lees, Nikolay V. Dimitrov, and Harry D.
Bear J Clin Oncol 162672-2685. Compared Pre vs
Post operative AC x 4 in operable breast tumors.
11
NSABP B27
Pre Post op chemo
12
NSABP B27
More response Better survival
13
Preoperative Chemotherapy in Primary Operable
Breast Cancer Results From the European
Organization for Research and Treatment of Cancer
Trial 10902By Jos A. van der Hage, Cornelis J.H.
van de Velde, Jean-Pierre Julien, Michelle
Tubiana-Hulin, Cecile Vandervelden, Luc
Duchateau, and Cooperating InvestigatorsJ Clin
Oncol 194224-4237.FEC60 x 4 pre vs post op
14
Prospective Evaluation of Paclitaxel Versus
Combination Chemotherapy With Fluorouracil,
Doxorubicin, and Cyclophosphamide as Neoadjuvant
Therapy in Patients With Operable Breast
Cancer By Aman U. Buzdar, S. Eva Singletary,
Richard L. Theriault, Daniel J. Booser, Vicente
Valero, Nuhad Ibrahim, Terry L. Smith, Lina
Asmar, Debra Frye, Nikki Manuel, Shu-Wan Kau,
Marsha McNeese, Eric Strom, Kelly Hunt, Frederick
Ames, and Gabriel N. Hortobagyi J Clin Oncol
173412-3417.
15
Weekly (wkly) paclitaxel (P) followed by FAC as
primary systemic chemotherapy (PSC) of operable
breast cancer improves pathologic complete
remission (pCR) rates when compared to every
3-week (Q 3 wk) P therapy (tx) followed by FAC-
final results of a prospective phase III
randomized trial.Marjorie C Green, Aman U
Buzdar, Terry Smith, Nuhad K Ibrahim, Vicente
Valero, Marguerite Rosales, Massimo
Cristofanilli, Daniel J Booser, Lajos Pusztai,
Edgardo Rivera, Richard Theriault, Cynthia
Carter, Sonja E Singletary, Henry M Kuerer, Kelly
Hunt, Eric Strom, Gabriel N Hortobagyi Proc Am
Soc Clin Oncol 21 2002 (abstr 135)

• Pathologic Complete Remission Rates (Breast and
  Lymph Nodes) Weekly vs. Q 3 Week Paclitaxel
• Node Positive Node Negative 
• Weekly (n 50) Q 3 Week (n 51) Weekly (n
  68) Q 3 Week (n 67)
• pCR 14 (28) 7 (13.7) 20 (29.4) 9 (13.4)

Weekly Paclitaxel is superior to q 3 weeks.
16
The Effect on Tumor Response of Adding Sequential
Preoperative Docetaxel to Preoperative
Doxorubicin and Cyclophosphamide Preliminary
Results From NationalSurgical Adjuvant Breast
and Bowel Project Protocol B-27By Harry D. Bear,
Stewart Anderson, Ann Brown, Roy Smith,
Eleftherios P. Mamounas, Bernard Fisher, Richard
Margolese, Heather Theoret, Atilla Soran, D.
Lawrence Wickerham, and Norman WolmarkJ Clin
Oncol 214165-4174.
17
(No Transcript)
18
Clinical and pathologic complete response are
not concordant AC T achieves a higher CR and
PR ER tumors do not respond as well as ER-
tumors (about half as well)
19
Neoadjuvant chemotherapy in breast cancerH.
Charfare, S. Limongelli and A. D.
PurushothamBritish Journal of Surgery 2005 92
1423
20
Neoadjuvant systemic therapy for breast cancer
an overview and review of recent clinical
trialsEmer O Hanrahan, Bryan T Hennessy
Vicente ValeroExpert Opin. Pharmacother. (2005)
6(9)1477-1491
21
(No Transcript)
22
Recommendations From an International Expert
Panel on the Use of Neoadjuvant (Primary)
Systemic Treatment of Operable Breast Cancer An
UpdateManfred Kaufmann, Gabriel N. Hortobagyi,
Aron Goldhirsch, Suzy Scholl, Andreas
Makris,Pinuccia Valagussa, Jens-Uwe Blohmer,
Wolfgang Eiermann, Raimund Jackesz, Walter Jonat,
Annette Lebeau, Sibylle Loibl, William Miller,
Sigfried Seeber, Vladimir Semiglazov, Roy Smith,
Rainer Souchon, Vered Stearns, Michael Untch, and
Gunter von MinckwitzJ Clin Oncol 241940-1949
23
Response to primary chemotherapy in breast cancer
patients with tumorsnot expressing estrogen and
progesterone receptorsM. Colleoni,1 I.
Minchella,1 G. Mazzarol,2 F. Nole,1 G.
Peruzzotti,1 A. Rocca,1 G.Viale,2L. Orlando,1 G.
Ferretti,1 G. Curigliano,1 P.Veronesi,3 M. Intra3
A. Goldhirsch1Annals of Oncology 11
1057-1059. 2000.
Predictors of response include ER/PR negative and
high Ki-67
24
Recommendations From an International Expert
Panel on the Use of Neoadjuvant (Primary)
Systemic Treatment of Operable Breast Cancer An
UpdateManfred Kaufmann, Gabriel N. Hortobagyi,
Aron Goldhirsch, Suzy Scholl, Andreas
Makris,Pinuccia Valagussa, Jens-Uwe Blohmer,
Wolfgang Eiermann, Raimund Jackesz, Walter Jonat,
Annette Lebeau, Sibylle Loibl, William Miller,
Sigfried Seeber, Vladimir Semiglazov, Roy Smith,
Rainer Souchon, Vered Stearns, Michael Untch, and
Gunter von MinckwitzJ Clin Oncol 241940-1949
25
Primary Systemic Therapy of Breast CancerIrina
Sachelarie, Michael L. Grossbard, Manjeet Chadha,
Sheldon Feldman, Munir Ghesaniand Ronald H.
BlumOncologist 200611574-589
26
Recommendations From an International Expert
Panel on the Use of Neoadjuvant (Primary)
Systemic Treatment of Operable Breast Cancer An
UpdateManfred Kaufmann, Gabriel N. Hortobagyi,
Aron Goldhirsch, Suzy Scholl, Andreas
Makris,Pinuccia Valagussa, Jens-Uwe Blohmer,
Wolfgang Eiermann, Raimund Jackesz, Walter Jonat,
Annette Lebeau, Sibylle Loibl, William Miller,
Sigfried Seeber, Vladimir Semiglazov, Roy Smith,
Rainer Souchon, Vered Stearns, Michael Untch, and
Gunter von MinckwitzJ Clin Oncol 241940-1949
27
Letrozole Is More Effective Neoadjuvant Endocrine
Therapy Than Tamoxifen for ErbB-1
and/orErbB-2Positive, Estrogen
ReceptorPositive Primary Breast Cancer Evidence
From a Phase IIIRandomized TrialBy Matthew J.
Ellis, Andrew Coop, Baljit Singh, Louis Mauriac,
Antonio Llombert-Cussac, Fritz Janicke, William
R. Miller, Dean B. Evans, Margaret Dugan, Carolyn
Brady, Erhard Quebe-Fehling, and Mieke BorgsJ
Clin Oncol 193808-3816.
28
The relative efficacy of neoadjuvant endocrine
therapy versus chemotherapy in postmenopausalwome
n with ER positive breast cancerV. F.
Semiglazov, V. Semiglazov, V. Ivanov, A. Bozhok,
E. Ziltsova, R. Paltuev, G. Dashian, A. Kletzel,
E. Topuzov and L. Berstein Journal of Clinical
Oncology, Vol 22, No 14S 2004 519

• Methods 121 postmenopausal women with ER()
  and/or PgR() breast cancer T2N12, T3N01,
  T4N0M0 assigned to NAT with either CT Dox 60
  mg/m2 Pac 200 mg/m2, every 3 weeks, 4 cycles,
  n62 patients (pts), or HT with aromatase
  inhibitors, anastrazole 1 mg, n 30 pts, 3
  months).

In CT arm the most frequent grade III/IV toxicity
was alopecia ( 79.3 ), neutropenia ( 43.1 ),
cardiotoxicity (6.8 ), diarrhea (1.7). HT was
well tolerated. The most commonly adverse events
were hot flushes (23.3), vaginal discharge
(6.6), musculosskeletal disorders (1.7).
Note this does not give the pathologic CR rate.
29
Conclusions

• Neoadjuvant therapy
• Increases the likelihood of breast conservation
  somewhat.
• Does not adversely affect survival excepting a
  small risk of locoregional failure.
• More is likely better i.e. add the taxane
• Endocrine receptor status will affect the outcome
  and may need to be treated upfront, but chemo has
  more robust data.
• Randomized comparison of endocrine vs chemo vs
  both is currently lacking for the ER/PR pt.

30
NCCN

• Inoperable locally advanced breast cancer
  (clinical stage IIIA except for T3N1M0,
  clinical stage IIIB, or clinical stage IIIC)
• For patients with inoperable locally advanced
  disease at presentation, the initial use of
  anthracycline-based preoperative chemotherapy is
  standard therapy.
• Local therapy after preoperative therapy usually
  consists of (1) total mastectomy with axillary
  lymph node dissection, with or without delayed
  breast reconstruction, or (2) lumpectomy and
  axillary dissection. Both local treatment groups
  are considered to have sufficient risk of local
  recurrence to warrant the use of chest wall (or
  breast) and supraclavicular node irradiation. If
  internal mammary lymph nodes are involved, they
  should also be irradiated.
• In the absence of detected internal mammary node
  involvement, consideration may be given to
  including the internal mammary lymph nodes in the
  RT field.
• Patients with an inoperable stage III tumor with
  disease progression during preoperative
  chemotherapy should be considered for palliative
  breast irradiation in an attempt to enhance local
  control.
• In all subsets of patients, further systemic
  adjuvant chemotherapy after local therapy is felt
  to be standard.

31
Issues

• SLN biopsy probably needs to be done upfront.
• Tumor shrinkage is not uniform.
• Tumor imaging is not very accurate.
• Overselling the shrink may lead to patient
  anxiety and dissatisfaction.
• What therapy is needed adjuvantly for those
  without a CR?
• Our patient?

32
Does a cCR need surgery?

• Is Surgery Necessary After Complete Clinical
  Remission Following Neoadjuvant Chemotherapy for
  Early Breast Cancer?
• By A. Ring, A. Webb, S. Ashley, W.H. Allum, S.
  Ebbs, G. Gui, N.P. Sacks, G. Walsh, and I.E.
  Smith
• J Clin Oncol 214540-4545