# Radiation Oncology/Breast/Breast chemotherapy

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* NSABP trials
A comprehensive discussion of chemotherapy should be reserved for an Oncology textbook, but general principles of chemotherapy and how it's used with radiation therapy can be discussed here.

## Adjuvant Chemo -> RT vs RT -> Chemo

* Harvard
** Randomized. 244 pts. Randomized to RT before chemo vs chemo before RT. Chemo was cyclophosphamide, doxorubicin, methotrexate, 5-FU, prednisone (CAMFP) x 12 weeks. 5-year local failure according to margin status - positive margins (14% XRT first, 25% chemo first), close margins <1 mm (0% vs 23%), negative margins (16% vs 0%), unknown margin status (0% vs 20%).
** 1996 PMID 8614420 — "The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer." Recht A et al. N Engl J Med. 1996 May 23;334(21):1356-61.
** 2005 PMID 15774786 — "Sequencing of chemotherapy and radiation therapy in early-stage breast cancer: updated results of a prospective randomized trial." Bellon JR et al. J Clin Oncol. 2005 Mar 20;23(9):1934-40. (Presented in abstract form at ASTRO 2001)
*** Median f/u 135 mo. No difference in local or distant failures. Longer time to DM with chemo: 25th percentile reached DF at 56 months (chemo first) vs 37 months (RT first).
*** No difference in any endpoint regardless of sequencing.

## Sequential Chemo -> RT vs. Concurrent Chemo-RT

* Italy (1997-2002)
** Randomized. 206 patients with quadrantectomy + ALND, pT1-2, SM-. Arm 1) sequential CMF -> RT vs. Arm 2) concurrent CMF + RT. RT given whole breast 50/20 + 10-15 Gy boost
** 2006 PMID 16226397 -- "A phase III randomized study on the sequencing of radiotherapy and chemotherapy in the conservative management of early-stage breast cancer." (Arcangeli G, Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):161-7. Epub 2005 Oct 13.)
*** Outcome: 5-year OS sequential 97% vs concurrent 98% (NS), DFS 86% vs. 87% (NS)
*** Toxicity: acute toxicity mild (NS); late toxicity being evaluated
*** Conclusion: RT can be delayed after completion of chemotherapy (up to 7 months in this study). Concurrent chemo-RT is safe
* ARCOSEIN trial (France) (1996-2000)
** Randomized. 716 pts, Stage I-II. Randomized to sequential CT then RT vs concurrent chemo/RT. Chemo was mitoxantrone + 5-FU + cyclophosphamide, 6 cycles q21d. RT 50 Gy/25 fx, optional 10-20 Gy boost.
** 2007 - PMID 17448869 — "Does concurrent radiochemotherapy affect cosmetic results in the adjuvant setting after breast-conserving surgery? Results of the ARCOSEIN multicenter, Phase III study: patients' and doctors' views." (Toledano A, Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):66-72.)
*** Patient assessment: 92% satisfactory or better. Physician assessment: 60% (concurrent) vs 85% (sequential) satisfactory.
*** Conclusion: Concurrent chemo-RT associated with greater differences between the breasts but no difference in patient satisfaction.
** Final results, 2007 - PMID 17264336 — "Phase III trial of concurrent or sequential adjuvant chemoradiotherapy after conservative surgery for early-stage breast cancer: final results of the ARCOSEIN trial." Toledano A et al. J Clin Oncol. 2007 Feb 1;25(4):405-10.
*** All patients: no difference in DFS (80%), LRFS (92% vs. 95%), DMFS (87% vs. 84%) or OS (90% vs. 91%)
*** Node positive: 5-year LRFS concurrent 97% vs. sequential 91% (SS)
** Late toxicity, 2006 PMID 16542788 -- "Concurrent administration of adjuvant chemotherapy and radiotherapy after breast-conserving surgery enhances late toxicities: long-term results of the ARCOSEIN multicenter randomized study." (Toledano A, Int J Radiat Oncol Biol Phys. 2006 Jun 1;65(2):324-32.)
*** Subset of 214 pts assessed by survey. Physical exam and assessment of toxicity using LENT-SOMA scale for breast.
*** Increased fibrosis, telangectasia, hyperpigmentation, and atrophy in concurrent chemo/RT arm. No difference in pain, breast edema, lymphedema.
** 2004 - PMID 15093200 — "[Radiation and concomitant chemotherapy after surgery for breast cancer]" (French) Calais G et al. Cancer Radiother. 2004 Feb;8(1):39-47.
** Conclusion: Appealing option for women at high risk of recurrence (node positive). But, increased grade 2 or higher late effects.
Non-randomized studies:
* Harvard
** 2006 - PMID 16243442 — "Prospective evaluation of concurrent paclitaxel and radiation therapy after adjuvant doxorubicin and cyclophosphamide chemotherapy for Stage II or III breast cancer." (Burstein HJ, Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):496-504.)
*** Prospective, non-randomized. 40 pts. Treated with adjuvant AC x 4, then concurrent taxol (weekly or q3week) + RT. 26 pts intact breast, 14 pts post-mastectomy. Breast dose: 39.6 Gy + boost to 49.6-55.6 Gy. Chest wall: 45 Gy + boost to 49-55 Gy.
*** Dose limiting toxicity in 25%(4 of 16) receiving weekly taxol. In pts receiving q3w taxol, DLT not reached. Grade 2 pneumonitis in 8% (q3w taxol).
*** Concurrent RT with weekly taxol is not feasible after AC chemotherapy.

## Adjuvant chemotherapy

* CMF (cyclophosphamide, methotrexate, 5-FU)
* Adriamycin-based
* FEC (5-FU, epirubicin, cyclophosphamide)

### Sequential vs alternating

* NCI Milan - CMF + Adriamycin
** 403 pts. 4 or more nodes. CMF and Adriamycin q3weeks over 36 weeks. Randomized to sequential chemotherapy (Adriamycin x 4 followed by CMF x 8) vs alternating (2 cycles of CMF alternating with 1 cycle of Adriamycin for 12 total cycles).
** 10-year results: PMID 7837388 — "Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results." Bonadonna G et al. JAMA. 1995 Feb 15;273(7):542-7.
*** Improved relapse free survival (42% vs 28%) and overall survival (58% vs 44%) for sequential chemotherapy.
** Conclusion: benefit for sequential CMF/Adria chemotherapy over alternating chemotherapy. This may be due to giving each chemotherapy drug in a "dose-dense" fashion rather than spreading it out over time.

### Sequential vs. concurrent

* INT-0137 -- concurrent AC vs. sequential dose-intense AC
** Randomized. 3176 patients s/p surgery, with high-risk N0 or low-risk N+ treated with AC. Randomized to concurrent AC (doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 Q3W x 6 cycles) vs. sequential AC (doxorubicin 40.5 mg/m2 Q3W x 4 cycles followed by cyclophosphamide 2.4 g/m2 Q2W x 3 cycles). Same dose, but higher intensity in sequential arm
** 2007 PMID 17308269 -- "Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313)." (Linden HM, J Clin Oncol. 2007 Feb 20;25(6):656-61.)
*** 5-year outcome: OS 88% vs. 89% (NS)
*** Toxicity: hematologic grade 4 greater with A -> C, nonhematologic comparable
*** Conclusion: Trial does not support dose-intense sequenced therapy

## Neoadjuvant chemotherapy

* General principles: neoadjuvant chemotherapy for breast cancer is chemotherapy given before local therapy (surgery or radiation).
* Advantages: In comparison to chemotherapy given after surgery (adjuvant chemotherapy), neoadjuvant chemotherapy has certain theoretical advantages:
** Reduces tumor volume prior to surgery, which may allow for breast conserving surgery rather than mastectomy.
** Early systemic therapy. Instead of having chemotherapy delayed by several months due to the need for scheduling of surgery and waiting for wound healing, chemotherapy can be given without delay, thus treating micrometastatic disease earlier.
** Allows in vivo assessment of the chemotherapeutic drug's effectiveness. If the tumor decreases in size after chemotherapy then the oncologist will know the drug is effective. If the tumor does not decrease in size, then the oncologist can switch to a different drug.
** Improved tumor vascularity before surgery may allow more of the drug to reach the area around the tumor.
* Several randomized trials suggested benefit for neoadjuvant chemotherapy, but flaws in design resulted in no difference between arms
* NSABP B-18 trial demonstrated benefit of neoadjuvant chemotherapy (AC) on higher rates of breast conservation surgery, without impacting DFS or OS. Unfortunately, only 13% patients reached pathological CR
* NSABP B-27 trial showed the addition of docetaxel to AC did not improve DFS or OS, but improving pCR (10% to 19%) and decreasing local recurrence rate (8% to 5%). Grade 4 toxicity increased (10% to 23%)
* Please see the Post-mastectomy RT section for information about the role of RT after neoadjuvant chemo and mastectomy
* NSABP B-27 (1995-2000) - Preop AC alone vs Preop ACT vs. Preop AC + postop docetaxel
** Randomized, 3 arms. 2353 women, only palpable disease allowed (breast or axilla). If primary breast, >1cm (T1c-T3N0-1); any size with axillary adenopathy (T1-3N1). Arm 1) Neoadjuvant AC x4 cycles vs. Arm 2) Neoadjuvant AC x4 then neoadjuvant docetaxel x4 vs. Arm 3) Neoadjuvant AC x4 followed by surgery then adjuvant docetaxel x4. Surgery was lumpectomy + ALDN or mastectomy. All pts received tamoxifen x 5 yrs regardless of ER/PR status. Measurement of tumor (by physical exam) prior to each chemo and before surgery. PMRT not permitted.
** Preliminary; 2003 PMID 14559892 — "The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27." (Bear HD, J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14.)
*** Outcome: Higher overall response (CR+PR) for pre-op AC+T group vs AC (90.7% vs 85.5%); higher cCR rate (63% v 40%). No difference in breast conservation rate.
*** Toxicity: Grade 4 AC 10% vs. docetaxel 23%
*** Conclusion: Addition of preop docetaxel significantly increased clinical and pathologic response rates; no impact on BCS
** 6-years; 2006 - PMID 16606972 — "Sequential Preoperative or Postoperative Docetaxel Added to Preoperative Doxorubicin Plus Cyclophosphamide for Operable Breast Cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27" Bear HD et al. J Clin Oncol. 2006 May 1;24(13):2019-27. Median F/U 6.5 years
*** Outcome: pCR AC 9% vs. ACT 19% vs. AC-S-T 10% (SS). LR 8% vs. 5% vs. 5% (SS) Of LR, ~50% were IBTR in women with BCT, other half presumably CW recurrence; regional recurrence all groups 2% (NS); No difference in DFS or OS.
*** Conclusion: Addition of docetaxel no impact on DFS or OS, improved pCR and first LR rate
** 8-years; 2008 PMID 18258986 -- "Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27." (Rastogi P, J Clin Oncol. 2008 Feb 10;26(5):778-85.) Median F/U 8.5 years
*** Outcome: pCR AC (AC and AC-S-T) 13% vs. ACT 26% (SS); OS 5-year 82-83% (NS), 8-year 74-75% (NS); DFS 5-year 68-71% (NS); 8-year 59-62% (NS). Having pCR significant predictor for DFS and OS
*** Recurrence: IBTR AC 7% vs. ACT 6% vs. AC-S-T 5% (NS); chest wall 4% vs. 2% vs. 3% (NS); regional 3% vs. 2% vs. 3%. Overall taxotere regimens had (SS) fewer first local recurrences
*** Conclusion: Neoadjuvant chemotherapy comparable to adjuvant therapy, and may allow BCS for patients who may not otherwise be candidates
* NSABP B-18 (1988-1993) - neoadjuvant AC versus postop AC
** Randomized. 1523 patients. T1-3N0-1 "operable, palpable, non-fixed" (Stage I-IIIA but no cN2 disease). Arm 1) ADJ: Surgery (lumpectomy + ALND or radical mastectomy) followed by 4 cycles doxorubicin and cyclophosphamide (AC) every 21 days, vs. Arm 2) NEO: Same chemotherapy neoadjuvantly, followed by surgery. Surgeons required to state intended surgical procedure at randomization. Tamoxifen x 5 years for age 50+, regardless of ER/PR. In NEO group, pts received breast and lymph node measurement by physical exam before each chemo cycle and before surgery. For lumpectomy group, XRT was given after surgery in the preop group and after chemo in the postop group. No PMRT allowed. cT1 ~30%, cN0 ~75%
** 1997 PMID 9215816 -- "Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18." (Fisher B, J Clin Oncol. 1997 Jul;15(7):2483-93.)
*** Subset analysis. 747 women who received neoadjuvant chemo.
*** Outcome: Breast: cCR 36%. In women with cCR, pCR in 26% (or 9% pCR overall). pCR by cStage: cT1 14%, cT2 9%, cT3 4%. Lymph Nodes: cCR 73%. In women with cCR, pCR in 44% (or 32% pCR overall).
*** Frequency of lumpectomy: NEO proposed 65% vs. performed 67%; ADJ proposed 66% vs. performed 60%. Performed NEO 67% vs. ADJ 60% (SS). Overall 12% more lumpectomies performed. If T3 22% vs. 8% (SS), if T2 71% vs. 63%
*** Conclusion: Preop therapy reduced tumor bulk; 12% more lumpectomies were performed, mostly in tumors >=5 cm. Recommend preop chemo only if lumpectomy not feasible initially or if cosmetic concerns
** 5-years; 1998 PMID 9704717
*** Outcome: 80% had a decrease in tumor size after chemo. 36% had cCR. 26% with cCR had pCR. Nodal response in 89%: 73% with cCR and 44% pCR. More patients underwent lumpectomy after preop chemo versus postop (67.8% vs 59.8%): increase of 12% in lumpectomies performed. Greatest increase for pts with tumors >5 cm (175% increase). Similar rate of ipsilateral breast recurrence after lumpectomy.
** 9-years; 2001 PMID 11773300 - "Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18." Wolmark N et al. J Natl Cancer Inst Monogr. 2001;(30):96-102.
*** Outcome: OS 5-years 81% vs 80% (NS), 9-years OS 70% vs 69% (NS); DFS 5-years both 67% (NS), 9-year DFS 53-55%). No difference in rates of relapse at different sites. cCR in 36% but only 13% with pCR.
*** Statistically signif. association between clinical response (by physical exam) to neoadj. chemo and survival — 9-year OS 78% for pts with cCR, 67% with cPR , 65% for cNR (defined as stable or progressive dz). DFS was 64%, 54%, 46%. Also, improved OS for those with a pathologic CR versus those with a cCR but residual invasive disease after surgery: 85% vs 73%. Pathologic LN status and primary tumor response are independent factors for OS and DFS.
** Pathology; 2002 PMID 12209710
*** Conclusion: tumor regression during neoadjuvant treatment may be a surrogate marker for outcome.
** 16-years; 2008 PMID 18258986 -- "Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27." (Rastogi P, J Clin Oncol. 2008 Feb 10;26(5):778-85.) Median F/U 16 years
*** Outcome: Ability to undergo BCS NEO 68% vs. ADJ 60% (SS); pCR 13%; OS 5-year 81% vs. 80% (NS), 8-year both 72% (NS), 16-year both 55%; DFS 5-year both 67% (NS), 8-year 58% vs. 55 (NS), 16-year 42% vs. 39% (NS). Having pCR significant predictor for DFS and OS
*** By subset: age <50 trend for improved survival with neoadjuvant 16-years 61% vs. 55% (p=0.06); age >50 trend for improved survival with adjuvant 16-year 50% vs. 55% (p=0.07)
*** Recurrence: IBTR (only if lumpectomy) NEO 13% vs. 10% (NS); chest wall both 3% (NS); regional 4% vs. 5% (NS); contralateral 5% vs. 6% (NS)
*** Conclusion: Neoadjuvant chemotherapy comparable to adjuvant therapy, and may allow BCS for patients who may not otherwise be candidates
* EORTC trial - ??
Prognosis
* Royal Marsden; 2008 PMID 18592370 -- "The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer." (Jones RL, Breast Cancer Res Treat. 2008 Jul 1. [Epub ahead of print])
** Retrospective. Matched cohort, 103 patients s/p neoadjuvant chemotherapy
** Predictors for RFS/OS: only Ki-67 significant; not significant age, menstrual status, T stage, N stage, operability, ER, PR, Her2, Grade, histology, LVI, tumor size. 5-year RFS lowest Ki-67 tertile 77% vs. highest tertile 27% (SS); 5-year OS 93% vs. 39% (SS)
** Conclusion: Post-chemo Ki-67 strong predictor of outcome
Review
* NCI Symposium; 2008 PMID 18258988 -- "Statement of the science concerning locoregional treatments after preoperative chemotherapy for breast cancer: a National Cancer Institute conference." (Buchholz TA, J Clin Oncol. 2008 Feb 10;26(5):791-7.)
** Review of evidence for imaging and loco-regional therapy in patients receiving preop chemotherapy
** Initial workup: initial imaging critical, role for MRI unclear, axillary U/S-guided FNA should be considered
** Timing of SLND: False negative rate after induction ~10%, comparable to de novo SLND. However, role of SLND in clinically positive patients is unclear
** BCS: possible more frequently with carefully selected patients
** RT: Studies evaluating benefit of PMRT after neoadjuvant chemo are small and retrospective

## Chemotherapy with hormonal therapy

* NSABP B-20, 1997 - chemotherapy + tamoxifen vs tamoxifen alone
** 2306 pts. Randomized to: 1) TAM alone, 2) Methotrexate, 5-FU, tamoxifen (MFT), or 3) CMF + tamoxifen (CMFT).
** PMID 9390536 — "Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer." Fisher B et al. J Natl Cancer Inst. 1997 Nov 19;89(22):1673-82.
*** 5 years f/u. Improved DFS for chemotherapy + tam vs tam alone (90% for MFT, 89% for CMFT, and 85% for TAM; S.S.), improved distant disease free survival (92% v 91% v 87%), overall survival (97% for MFT versus 94% for tamoxifen [P = .05]; 96% for CMFT versus 94% for tamoxifen [P = .03], reduced ipsilateral breast tumor recurrence,
** Conclusion: chemotherapy still has a benefit even when tamoxifen is used
* Institut Gustave-Roussy (1989-96)
** PMID 12196363 Full text, 2002 — "Patterns of failure in a randomized trial of adjuvant chemotherapy in postmenopausal patients with early breast cancer treated with tamoxifen." Arriagada R et al. Ann Oncol. 2002 Sep;13(9):1378-86.
** Randomized. 835 pts. Included postmenopausal pts who were N+ or grade II-III. Randomized to tamoxifen vs tamoxifen + chemotherapy. Chemo was 6 cycles of FAC or FEC. Pts were treated with lumpectomy or mastectomy.
** 5-yr DFS 73% (TAM) vs 79% (TAM-CT), p=0.06. 5-yr OS 82% vs 87%, p=0.06. 5-yr DM 22% vs 16% (S.S.). No difference in LC. Chemotherapy more effective in pts who were ER+.
** Conclusion: chemotherapy is effective in postmenopausal pts receiving tamoxifen.

## Taxane-based chemotherapy

* Intergroup 0148 / CALGB 9344 - PMID 12637460 — "Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer." Henderson IC et al. J Clin Oncol. 2003 Mar 15;21(6):976-83.
** 3121 pts. Randomized to 4 cycles AC +/- 4 cycles Taxol, each given q3weeks, total of 24 weeks.
** Addition of Taxol to AC after surgery improves OS in node positive cancers: DFS 70% vs 65%, OS 80% vs 77% at 5-years.
* NSABP B-28, 2005 (1995-98) - AC x 4 +/- Taxol x 4. node-positive.
** PMID 15897552 — "Paclitaxel After Doxorubicin Plus Cyclophosphamide As Adjuvant Chemotherapy for Node-Positive Breast Cancer: Results From NSABP B-28." Mamounas EP et al. J Clin Oncol. 2005 Jun 1;23(16):3686-96.
** 3060 pts. cT1-3 with at least 1 positive node, treated with lumpectomy + node-dissection or mastectomy. Breast XRT (no axillary RT) after last cycle of chemo. No post-mastectomy RT. Tamoxifen allowed.
** 64 month median f/u. 5-year DFS 76% (AC/T) vs 72% (AC), S.S. No difference in 5-year OS, 85% in both arms.
Docetaxel:
* Breast Cancer International Research Group BCIRG 001, 2005 (1997-99) - PMID 15930421 — "Adjuvant docetaxel for node-positive breast cancer." (Martin M et al, N Engl J Med 352(22):2302-13,2005)
** 1480 pts. Node-positive, not fixed or matted (no cN2), T1-3. Randomized after surgery to TAC (taxotere, adriamycin, cyclophosphamide) vs FAC x 6 cycles q3weeks.
** Median f/u 55 m. 5-year DFS 75% (TAC) vs 68% (FAC). 28% reduction in relapse. 30% lower risk of death. OS 87% vs 81%.

### Dose-dense chemotherapy

* Intergroup / CALGB 9741, 2003
** 2005 pts. Node positive. Every 2 weeks AC/T vs standard dose q3weeks. 2x2 factorial design. Randomized to: Sequential A x 4 -> T x 4 -> C x 4 q3week / 36 wks, Sequential A->T->C q2week / 24 wks, Concurrent AC x 4 -> T x 4 q3w / 24 wks, or Concurrent AC x 4 -> T x 4 q2week / 16 wks. Filgrastim (G-CSF) given with dose-dense chemo.
** First report: PMID 12668651
*** 7% improvement in DFS (82% vs 75%) for dose-dense (RR=0.74), 2% OS at 3 years (RR=.69). No difference between concurrent and sequential arms. Less neutropenia, less need for hospitalization, and lower incidence of other toxicities with the dose-dense approach.

## Stem-Cell Transplant

* SWOG 9623
** 2007 PMID 17404368 -- "Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study 9623." (Moore HC, J Clin Oncol. 2007 May 1;25(13):1677-82.)
*** Randomized. 536 patients, BCA s/p lumpectomy/mastectomy, with >=4 LN+. Treated with 1) AC-HD vs. 2) ATC
*** 5-year outcome: No difference in OS (88% vs. 84%) or DFS (80% vs. 75%)
*** Conclusion: transplantation not superior to dose-dense dose-escalated therapy, higher toxicity

## Meta-analysis

* Early Breast Cancer Trialists' Collaborative Group (a.k.a. Oxford overview) - Meta-analysis of chemotherapy
    See also: Oxford overview of Radiotherapy or Hormonal therapy
** Early results, 1988 - PMID 3205265 — "Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women." N Engl J Med. 1988 Dec 29;319(26):1681-92.
*** 61 trials. 28,896 women.
** 1992 - PMID 1345869 — "Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women."
*** 131 trials. 75,000 women.
** 1998 - PMID 9752815 — "Polychemotherapy for early breast cancer: an overview of the randomised trials." Lancet. 1998 Sep 19;352(9132):930-42.
*** Prolonged polychemotherapy vs no chemo (47 trials, 18,000 women); long vs short polychemo (11; 6,000); anthracycline-based vs CMF (11; 6,000).
*** Polychemo: reduced recurrences by 35% (age < 50), 20% (age 50-69); mortality 27% (<50), 11% (50-69). Recurrence reductions in first 5 years. Survival benefit grew during first 10 yrs. Results in 10-year OS difference for node-negative pts 71% vs 78% (absolute 7% gain) or 42% vs 53% (11% benefit) for node-positive. Smaller benefit for age > 50.
*** No advantage for more than 3-6 months of chemo. Anthracycline-based better than CMF for recurrence and survival (69% vs 72% 5-yr OS
** 2005 - PMID 15894097 — "Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials." Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2005 May 14-20;365(9472):1687-717.
* Her2 and Anthracyclines
** 2008 PMID 18159072 -- "HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials." (Gennari A, J Natl Cancer Inst. 2008 Jan 2;100(1):14-20. Epub 2007 Dec 25.)
*** Pooled analysis, 8 trials, 6564 patients, 5354 with her2 info available, 29% her2+.
*** Her2+ patients: anthracycline-based chemo superior to non-anthracyclines in DFS (HR 0.71, SS) and OS (HR 0.73, SS)
*** Her2- patients: no impact of anthracyclines on DFS (HR 1.00, NS) or OS (HR 1.03, NS)
*** Conclusion: Added benefit of adjuvant anthracyclines appears confined to women with her2 overexpression

## Herceptin (trastuzumab)

Known to improve time to progression in metastatic disease in pts with her-2-neu overexpressing tumors when combined with standard chemotherapy.
Adjuvant setting:
* M.D.Anderson, 2005 (2001-3) - Herceptin plus Taxol/FEC chemotherapy. Evaluate pCR.
** PMID 15738535 — "Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, Paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer." Buzdar AU et al. J Clin Oncol. 2005 Jun 1;23(16):3676-85.
** 42 pts. Stage II-IIIA, Her-2-neu 3+ or positive by FISH. Taxol x 4, then FEC x 4 then surgery + RT. Randomized to +/- weekly Herceptin x 24 weeks concurrent with first chemotherapy cycle.
** pCR in 26% (chemo) vs 65.2% (Herceptin). Trial stopped early
* NSABP B-31 and NCCTG N9831, 2005
** NSABP B-31 (2000-05)
*** Operable breast cancer, Her-2 positive with LN+. Required FISH amplification or 3+ by immunohistochemistry. Required axillary dissection.
*** Two arms: 1) ACx4 -> Taxol x 4, 2) Same chemo + Herceptin weekly x 1 yr (beginning with first Taxol dose). Taxol was q3w (in 90%). Herceptin 2 mg/kg.
** NCCTG N9831 (2000-05)
*** Also enrolled high-risk node-negative disease (as of 2003) - >2 cm and ER+ or PR+, or >1 cm and ER-/PR-. Allowed sentinal lymph node.
*** Three arms: 1) ACx4 -> weekly Taxol x 12, 2) ACx4 -> weekly Taxol x 12 -> Herceptin 1 yr, 3) ACx4 -> Taxol + Herceptin (started together)
** The two trials had some minor differences in the sequencing of Taxol, hormonal therapy, and RT, but were quite similar.
** Combined results:
*** Interim; 2005 PMID 16236738 Full text — "Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer." Romond EH et al. N Engl J Med. 2005 Oct 20;353(16):1673-84.
**** Interim analysis of 2043 pts (of planned 2700) in B-31 and 1633 (of 2000) in NCCTG.
**** 3-yr DFS improved by 12% in Herceptin arms. Risk of death decreased by 33%. Up to 4.1% incidence of NYHA Class III-IV heart failure. 8% decrease in DM. Isolated brain metastases more common in herceptin group. Sequential administration of H may be inferior to concurrent administration with chemo.
*** 4-years; 2011 PMID 21768458 -- "Four-Year Follow-Up of Trastuzumab Plus Adjuvant Chemotherapy for Operable Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Joint Analysis of Data From NCCTG N9831 and NSABP B-31." (Perez EA, J Clin Oncol. 2011 Jul 18. [Epub ahead of print])
**** Significant reduction in DFS and 39% reduction in deaths.
** Cardiac dysfunction; 2005 PMID 16258083 — "Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31." Tan-Chiu E et al. J Clin Oncol. 2005 Nov 1;23(31):7811-9.
** Concurrent H+RT; 2009 PMID 19349549 -- "Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831." (Halyard MY, J Clin Oncol. 2009 Jun 1;27(16):2638-44. Epub 2009 Apr 6.)
*** Subset analysis of 1503 patients. No RT to IM nodes. Median F/U 3.7 years
*** Outcome: No difference for acute skin reaction, pneumonitis, dyspnea, cough, dysphagia, or neutropenia. Worse leukopenia for AC-TH vs AC-T (OR 1.9). No difference of cardiac events, regardless of side (cumulative incidence ~2.5%)
*** Conclusion: Concurrent adjuvant RT and herceptin not associated with increased acute adverse effects
* Herceptin Adjuvant (HERA), 2005 (2001-05) - also called BIG (Breast International Group) 01-01
** 5081 pts. LN+ or LN- and >1 cm. Pts randomized after completing adjuvant therapy. Had to have a minimum of 4 cycles.
*** Randomized to 1) observation, 2) 1 year, or 3) 2 years of Herceptin. Herceptin given q3w (at 6 mg/kg).
** Results:
*** PMID 16236737, 2005 Full text — "Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer." Piccart-Gebhart MJ et al. N Engl J Med. 2005 Oct 20;353(16):1659-72.
**** Interim analysis performed for the one year treatment group. 2-yr DFS improved 8.4%, 50% reduction. No difference in OS. 33% developed brain mets.
*** 2-yr update: PMID 17208639, 2007 — "2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial." Smith I et al. Lancet. 2007 Jan 6;369(9555):29-36.
**** After a median follow-up of 2 years there is a significant overall survival benefit for adjuvant trastuzumab. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab compared with observation alone was 0.66 (95% CI 0.47-0.91; p=0.0115).
* FinHer, 2006 (2000-2003)
** 232 women, LN+ or high risk LN- (tumor > 2 cm and ER/PR-), with amplified HER2/neu gene. Randomized to 9 weekly trastuzumab cycles vs no trastuzumab concurrent with chemotherapy (docetaxel or vinorelbine x 3 cycles q3w (weeks 1,4,7) +/- trastuzumab, followed by FEC (flurouracil, epirubicin, and cyclophosphamide) x 3 cycles q3w).
** Note: The her2neu+ randomization was a subset of a larger trial of 1010 women total, randomized to docetaxel vs vinorelbine followed by FEC, as above.
** Results:
*** PMID 16495393, 2006 — "Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer." Joensuu H et al. N Engl J Med. 2006 Feb 23;354(8):809-20.
**** 3-year recurrence-free survival better in those who received trastuzumab (89 percent vs. 78 percent; P=0.01). Trastuzumab was not associated with decreased left ventricular ejection fraction or cardiac failure.

## CDK4/6 Inhibitors

* Approved CDK4/6 Inhibitors:
** Palbociclib (Ibrance): Approved for the treatment of HR+/HER2- advanced or metastatic breast cancer in combination with hormone therapy.
** Ribociclib (Kisqali): Approved for HR+/HER2- advanced or metastatic breast cancer in combination with hormone therapy.
** Abemaciclib (Verzenio): Approved for HR+/HER2- advanced or metastatic breast cancer as monotherapy or in combination with hormone therapy.
* Tim Dukelow et al. CDK4/6 inhibitors in breast cancer. Anticancer Drugs. 2015 Sep;26(8):797-806. (PMID: 26053278)
* Laura M Spring et al. CDK 4/6 Inhibitors in Breast Cancer: Current Controversies and Future Directions. Curr Oncol Rep. 2019 Feb 26;21(3):25. (PMID: 30806829)

## Multigene assays for risk assessment

* Oncogene DX
** Oncotype studies
** PMID 15591335, 2004 — "A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer." Paik S et al. N Engl J Med. 2004 Dec 30;351(27):2817-26.
*** Likelihood of distant recurrence in women with node-negative, ER-positive tumors. Studied 21 prospectively-identified genes. Cohort of 668 pts from NSABP B-14.
*** Conclusion: Positive validation study. Oncotype DX assay accurately predicts risk of DM.

## Erythropoietin

* Breast Cancer Erythropoietin Survival Trial (BEST) (Multi-national: Canada, Europe, Australia, South Africa)(2000-2002)
** Randomized. Stopped early due to adverse outcomes. 939 patients, metastatic breast CA. Arm 1) placebo vs. Arm 2) Epo to maintain Hgb 12-14 g/dL, and initiated if Hgb <13 g/dL
** 2005 PMID 16087945 -- "Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study." (Leyland-Jones B, J Clin Oncol. 2005 Sep 1;23(25):5960-72. Epub 2005 Aug 8.)
*** Outcome: 1-year OS placebo 76% vs. Epo 70% (SS); no difference in tumor response
*** Conclusion: Epo use to maintain high Hgb was associated with decreased survival