Sequencing of Therapy in Breast Cancer

Oncology & Hematology Review, 2014;10(1):33–6

Radiotherapy in the Neoadjuvant Setting
Radiation therapy delivered in advance of surgery would reduce delays between chemotherapy and radiotherapy, and similarly between surgery and radiation, and may therefore represent a favorable option. The question arises therefore, if neoadjuvant radiotherapy delivered after tumor chemosensitization, but in advance of definitive surgery, might offer an advantage over adjuvant radiotherapy. A number of large randomized phase III trials have confirmed the superiority of neoadjuvant radiotherapy over adjuvant radiotherapy in a number of other cancer sites, including rectal cancer35,36 and extremity soft tissue sarcoma.37,38 There are theoretical advantages in terms of timing, planning, and dosimetry. However, limited data exist on this therapeutic approach in the setting of breast cancer. Three recently completed prospective studies investigated the role of neoadjuvant radiation and taxane-based chemotherapy.39–41 In all studies, the regimen was found to be feasible and effective. A 20-year retrospective review of patients managed with neoadjuvant chemotherapy followed by neoadjuvant radiation in a single tertiary referral center in France found the approach to be oncologically safe and to facilitate immediate breast reconstruction while avoiding delays in mandatory radiation.42 A German study identified a survival advantage for neoadjuvant radiotherapy compared with adjuvant therapy in T2 tumors.43 A recent prospective study showed neoadjuvant chemotherapy and radiotherapy followed by mastectomy and immediate reconstruction to be equivalent to patients assigned to delayed reconstruction following completion of mastectomy and adjuvant chemoradiotherapy in terms of oncologic safety and cosmesis.44 These studies have been limited by small numbers and lack of standardization of chemotherapeutic regimes.

Neoadjuvant Radiotherapy Technique
One limitation in delivering chest wall irradiation in advance of surgical resection is the absence of pathologic prognostic information as regards nodal burden. Determination of exact number of nodes involved by metastatic disease, or indeed determining whether intra-thoracic nodal disease is present, is precluded by this approach. In light of this, we recommend a three-field approach to include delivery of radiotherapy to the whole breast and to the supraclavicular fossa. Computed tomography (CT) planning should be performed in advance of therapy to allow optimized targeting of therapy.

As outlined by Siewert et al.,45 there are numerous benefits to the delivery of radiotherapy and chemotherapy concomitantly, including organ preservation, radio-sensitization, and improved disease control. The treatment modalities exhibit ‘spatial co-operation,’ with radiotherapy acting to provide loco-regional control and chemotherapy against distant systemic micrometastases.46 Concomitant application of the modalities, however, may lead to increased toxicities.45 Sequential application of the treatments may facilitate the use of both at effective doses without increasing toxicity, and avoiding the need for dose reduction.

The most commonly applied drugs in neoadjuvant chemotherapeutic regimes include doxorubicin (Adriamycin®), paclitaxel (Taxol®), and cyclophosphamide. Doxorubicin has been used with efficacy in the radiosensitization of sarcoma; paclitaxel in non-small-cell lung cancer.45 It can be hypothesized therefore that these agents could also be applied as radio-sensitizing agents in breast malignancies. Commonly used radiosensitizing agents include cisplatin, which acts to interfere with doublestranded DNA (dsDNA) repair, and has been used with great efficacy in BRCA-1-associated triple negative breast cancer,47 a particularly challenging subtype. A certain subset of triple negative breast cancers can be deemed ‘basal-like’ by virtue of overexpression of epidermal growth factor receptor (EGFR), c-kit, and cytokeratin 5/6. These markers potentially represent targets for radio-sensitization. Sambade et al.48 investigated the use of lapatanib, a dual EGFR/Her2 kinase inhibitor, in combination with radiotherapy, in an in vivo murine model. Basal-like breast cancers exhibited complete resistance to lapatanib alone, but were shown to be highly growth impaired when radiation therapy was also applied. Similarly tumor control in Her-2 overexpressing subtypes was shown to be more pronounced when combination therapy was utilized compared with either modality in isolation. Tyrosine kinase inhibitors (TKIs), such as lapatinib, have also been shown to act in synergy with trastuzumab, and use of these agents together may further increase the efficacy of radiotherapy in Her2-positive subtypes.49

The luminal (hormone receptor-positive) subtypes of breast cancer have a more favorable prognosis than hormone receptor-insensitive tumors, which are associated with increased recurrence rates.50 In a series of patients undergoing breast conservation followed by adjuvant radiotherapy, Luminal A subtypes were shown to exhibit the lowest rates of loco-regional recurrence, followed by Luminal B subtypes.51 A Danish study also showed favorable response in hormone receptor-positive tumors to postmastectomy irradiation compared with hormone-negative subtypes.52 It has been hypothesized that estrogen-mediated acceleration between the G1 and S phases of the cell cycle impairs DNA damage repair mechanisms in tumor cells, enhancing radiation-mediated cell death. Hormone-sensitive tumors may therefore be particularly sensitive to radiotherapy.49,52

The role of radiotherapy in breast cancer is well validated, as is the use of neoadjuvant chemotherapy to render cancers operable or to facilitate breast conservation. We propose that neoadjuvant delivery of radiotherapy will have multiple benefits from oncologic and technical perspectives, as well as from a quality of life and patient satisfaction viewpoint, without increasing toxicity to an unacceptable level. Immediate breast reconstruction is the gold standard of care for patients requiring mastectomy. As disease-free and overall survival rates from breast cancer improve, quality of life and patient satisfaction become increasingly important. Delivery of adjuvant radiotherapy can disrupt the cosmesis of the reconstruction, negating the positive psychological effect of an immediate reconstruction. The presence of a prosthesis or an autologous flap may also make radiotherapy delivery technically challenging. Irradiation of the breast prior to surgery and reconstruction can improve delivery without compromising cosmetic results.

  1. Recht A, Edge SB, Solin LJ, et al., Postmastectomy radiotherapy: Clinical practice guidelines of the American Society of Clinical Oncology, J Clin Oncol, 2001;19:1539–69.
  2. National Institutes of Health Consensus Development Conference statement: adjuvant therapy for breast cancer, November 1–3, 2000, J Natl Cancer Inst Monographs, 2001;30:5–15.
  3. Carlson RW, Allred DC, Anderson BO, Metastatic breast cancer, version 1.2012: featured updates to the NCCN guidelines, J Natl Compr Canc Netw, 2012;10:821–9.
  4. Truong PT, Olivotto IA, Whelan TJ, et al., Clinical practice guidelines for the care and treatment of breast cancer: 16. Locoregional post-mastectomy radiotherapy, CMAJ, 2004;170:1263–73.
  5. Clarke M, Collins R, Darby S, et al., Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials, Lancet, 2005;366:2087–2106.
  6. Whelan TJ, Julian J, Wright J, et al., Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis, J Clin Oncol, 2000;18:1220–9.
  7. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, et al., Effect of radiotherapy after breastconserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10 801 women in 17 randomised trials, Lancet, 2011;378:1707–16.
  8. Whelan TJ, Olivotto I, Ackerman I, NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer, J Clin Oncol, 2011;29(Suppl.)LBA1003.
  9. Marks LB, Zeng J, Prosnitz LR, One to three versus four or more positive nodes and postmastectomy radiotherapy: Time to end the debate, J Clin Oncol, 2008;26:2075–7.
  10. Abdulkarim BS, Cuartero J, Hanson J, et al., Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy, J Clin Oncol, 2011;29:2852–8.
  11. Kunkler IH, Williams L, Prescott R, King CE, Effects of radiotherapy and surgery for early breast cancer, Lancet, 2006;367:1653–4.
  12. Fisher B, Bryant J, Wolmark N, et al., Effect of preoperative chemotherapy on the outcome of women with operable breast cancer, J Clin Oncol, 1998;16:2672–85.
  13. Mieog JSD, Van Der Hage JA, Van De Velde CJH, Preoperative chemotherapy for women with operable breast cancer, Cochrane Database Syst Rev, 2007;CD005002.
  14. von Minckwitz G, Untch M, Blohmer JU, et al., Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes, J Clin Oncol, 2012;30:1796–1804.
  15. Kaufmann M, von Minckwitz G, Bear HD, et al., Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: New perspectives 2006, Ann Oncol, 2007;18:1927–34.
  16. Gralow JR, Burstein HJ, Wood W, et al., Preoperative therapy in invasive breast cancer: Pathologic assessment and systemic therapy issues in operable disease, J Clin Oncol, 2008;26:814–9.
  17. Shannon C, Smith I, Is there still a role for neoadjuvant therapy in breast cancer?, Crit Rev Oncol Hematol, 2003;45:77–90.
  18. van Deurzen CH, Vriens BE, Tjan-Heijnen VC, et al., Accuracy of sentinel node biopsy after neoadjuvant chemotherapy in breast cancer patients: A systematic review, Eur J Cancer, 2009;45:3124–30.
  19. Shimazu K, Noguchi S, Sentinel lymph node biopsy before versus after neoadjuvant chemotherapy for breast cancer, Surg Today, 2011;41:311–6.
  20. Rozen WM, Ashton MW, Taylor GI, Defining the role for autologous breast reconstruction after mastectomy: Social and oncologic implications, Clin Breast Cancer, 2008;8:132–42.
  21. Heneghan HM, Prichard RS, Lyons R, et al., Quality of life after immediate breast reconstruction and skin-sparing mastectomy – A comparison with patients undergoing breast conserving surgery, Eur J Surg Oncol, 2011;37:937–43.
  22. Dutra AK, Neto MS, Garcia EB, et al., Patients’ satisfaction with immediate breast reconstruction with a latissimus dorsi musculocutaneous flap, J Plast Surg Hand Surg, 2012;46:349–53.
  23. Petersen A, Eftekhari ALB, Damsgaard TE, Immediate breast reconstruction: A retrospective study with emphasis on complications and risk factors, J Plast Surg Hand Surg, 2012;46:344–8.
  24. Robertson S, Wengström Y, Eriksen C, Sandelin K, Breast surgeons performing immediate breast reconstruction with implants – Assessment of resource-use and patient-reported outcome measures, Breast, 2012;21:590–6.
  25. Barry M, Kell MR, Radiotherapy and breast reconstruction: A meta-analysis, Breast Cancer Res Treat, 2011;127:15–22.
  26. Yin J, Yuan Z, Zhang X, Interaction between postmastectomy radiotherapy and immediate breast reconstruction, Chinese Clinical Oncology, 2012;39:418–20.
  27. Tran T, Tran T, Miles D, et al., The impact of radiation on surgical outcomes of immediate breast reconstruction, Am Surg, 2011;77:1349–52.
  28. Ho A, Cordeiro P, Disa J, et al., Long-term outcomes in breast cancer patients undergoing immediate 2-stage expander/ implant reconstruction and postmastectomy radiation, Cancer, 2012;118:2552–9.
  29. Cowen D, Gross E, Rouannet P, et al., Immediate postmastectomy breast reconstruction followed by radiotherapy: Risk factors for complications, Breast Cancer Res Treat, 2010;121:627–34.
  30. Christante D, Pommier SJ, Diggs BS, et al., Using complications associated with postmastectomy radiation and immediate breast reconstruction to improve surgical decision making, Arch Surg, 2010;145:873–8.
  31. Prabhu R, Godette K, Carlson G, et al., The impact of skin-sparing mastectomy with immediate reconstruction in patients with stage III breast cancer treated with neoadjuvant chemotherapy and postmastectomy radiation, Int J Radiat Oncol Biol Phys, 2012;82:e587–e593.
  32. Punglia RS, Saito AM, Neville BA, et al., Impact of interval from breast conserving surgery to radiotherapy on local recurrence in older women with breast cancer: retrospective cohort analysis, BMJ, 2010;340:c845.
  33. Motwani SB1, Strom EA, Schechter NR, et al., The impact of immediate breast reconstruction on the technical delivery of postmastectomy radiotherapy, Int J Radiat Oncol Biol Phys, 2006;66:76–82.
  34. Kronowitz SL, Robb GL, Radiation therapy and breast reconstruction: A critical review of the literature, Plast Reconstr Surg, 2009;124:395–408.
  35. Valentini V, van Stiphout RG, Lammering G, et al., Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials, J Clin Oncol, 2011;29:3163–72.
  36. Popek S, Tsikitis VL, Neoadjuvant vs adjuvant pelvic radiotherapy for locally advanced rectal cancer: Which is superior?, World J Gastroenterol, 2011;17:848–54.
  37. Davis AM, O’Sullivan B, Turcotte R, et al., Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma, Radiother Oncol, 2005;75:48–53.
  38. O’Sullivan B, Davis AM, Turcotte R, et al., Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: A randomised trial, Lancet, 2002;359:2235–41.
  39. Chakravarthy AB, Kelley MC, McLaren B, et al., Neoadjuvant concurrent paclitaxel and radiation in stage II/III breast cancer, Clin Cancer Res, 2006;12:1570–6.
  40. Formenti SC, Volm M, Skinner KA, et al., Preoperative twiceweekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: A phase I/II trial, J Clin Oncol, 2003;21:864–70.
  41. Bellon JR, Lindsley KL, Ellis GK, et al., Concurrent radiation therapy and paclitaxel or docetaxel chemotherapy in high-risk breast cancer, Int J Radiat Oncol Biol Phys, 2000;48:393–7.
  42. Monrigal E, Dauplat J, Gimbergues P, et al., Mastectomy with immediate breast reconstruction afterneoadjuvant chemotherapy and radiation therapy. A new option for patients with operableinvasive breast cancer. Results of a 20 years single institution study, Eur J Surg Oncol, 2011;37:864–70.
  43. Roth SL, Audretsch W, Bojar H, et al., Retrospective study of neoadjuvant versus adjuvant radiochemotherapy in locally advanced noninflammatory breast cancer: Survival advantage in cT2 category by neoadjuvant radiochemotherapy, Strahlenther Onkol, 2010;186:299–306.
  44. Giacalone PL, Rathat G, Daures JP, et al., New concept for immediate breast reconstruction for invasive cancers: Feasibility, oncological safety and esthetic outcome of post-neoadjuvant therapy immediate breast reconstruction versus delayed breast reconstruction: A prospective pilot study, Breast Cancer Res Treat, 2010;122:439–51.
  45. Siewert TY, Salama JK, Vokes EE, The concurrent chemoradiation paradigm – General principles, Nature, 2007;4:86–100.
  46. Steel GG, Peckham MJ, Exploitable mechanisms in combined radiotherapy-chemotherapy: the concept of additivity, Int J Radiat Oncol Biol Phys, 1979;5:85–91.
  47. Sikov WM, Neoadjuvant therapy for triple-negative breast cancer: The challenge of translating biological concepts into effective treatments, Curr Breast Cancer Rep, 2012;4:240–8.
  48. Sambade MJ, Kimple RJ, Camp JT, et al., Lapatinib in Combination With Radiation Diminishes Tumor Regrowth in HER2+ and Basal- Like/EGFR+ Breast Tumor Xenografts, Int J Radiat Oncol Biol Phys, 2010;77:575–81.
  49. Langlands FE, Horgan K, Dodwell DD, Smith L, Breast cancer subtypes: response to radiotherapy and potential radiosensitisation, Br J Radiol, 2013;86:20120601.
  50. Wang Y, Yin Q, Yu Q, et al., A retrospective study of breast cancer subtypes: The risk of relapse and the relations with treatments, Breast Cancer Res Treat, 2011;130:489–98.
  51. Nguyen PL, Taghian AG, Katz MS, et al., Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy, J Clin Oncol, 2008;26:2373–8.
  52. Kyndi M1, Sørensen FB, Knudsen H, et al., Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group, J Clin Oncol, 2008;26:1419–26.
Keywords: Breast cancer, radiotherapy, immediate reconstruction, neoadjuvant, postmastectomy irradiation