With node-negative, hormone receptor positive, HER2-negative breast cancer:
With low-risk recurrence scores (Oncotype Dx)
Is a selective estrogen receptor modulator (SERM) with antiestrogenic activity in breast tissue:
Reducing epithelial cell proliferation
Hot flashes are one of the most common and bothersome side effects of tamoxifen:
Up to 80% of women prescribed tamoxifen complain of hot flashes:
About 30% rate them as severe
Premenopausal women have a greater increase in hot flashes after starting tamoxifen:
Compared with perimenopausal or postmenopausal women
Hot flashes are believed to be due to a central nervous system antiestrogenic effect:
Causing thermoregulatory dysfunction
Additionally, some data suggest that polymorphisms in drug metabolizing enzymes (cytochrome P450 enzyme, CYP2D6):
Decrease the conversion of tamoxifen to its most active metabolite (endoxifen), and they may influence the likelihood of tamoxifen-related hot flashes
Coadministration of drugs that inhibit the activity of CYP2D6, such as the selective serotonin reuptake inhibitors (SSRIs) can reduce tamoxifen-related hot flashes
Among SSRIs, there is a gradient of potency for inhibition of CYP2D6; for example, paroxetine and fluoxetine are strong CYP2D6 inhibitors, while sertraline and duloxetine are moderate inhibitors
While the strong CYP2D6 inhibitors have the potential to adversely affect drug efficacy, the data to suggest that this issue decreases tamoxifen effect are very weak
Venlafaxine is a weak CYP2D6 inhibitor with proven efficacy against hot flashes without risk of significantly interfering with tamoxifen metabolism
References
Aiello Bowles EJ, Boudreau DM, Chubak J, Yu O, Fujii M, Chestnut J, Buist DS. Patient-reported discontinuation of endocrine therapy and related adverse effects among women with early-stage breast cancer. J Oncol Pract. 2012;8(6):e149-e157.
Ramaswami R, Villarreal MD, Pitta DM, Carpenter JS, Stebbing J, Kalesan B. Venlafaxine in management of hot flashes in women with breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat. 2015;152(2):231-237.
Johns C, Seav SM, Dominick SA, Gorman JR, Li H, Natarajan L, Mao JJ, et al. Informing hot flash treatment decisions for breast cancer survivors: a systematic review of randomized trials comparing active interventions. Breast Cancer Res Treat. 2016;156(3):415-426.
Is appropriate for many patients with locally advanced breast cancer regardless of subtype:
Because a response may allow both less extensive surgery and improved surgical outcomes
Locally advanced disease is defined as:
Stage III cancers
As well as the subset of IIB cancers with T3 disease
In addition, patients with earlier stage, HER2+ disease (stage I or II) may also be candidates for neoadjuvant therapy, if one or more of the following criteria apply:
The patient desires breast-conserving surgery (BCS) but is not a candidate for BCS or is likely to have a suboptimal cosmetic outcome with BCS due to tumor location or size relative to the size of the patient’s breast, and may be a better candidate if neoadjuvant therapy decreases the extent of her tumor
The patient has limited axillary nodal involvement (N1), for which axillary lymph node dissection would be standard surgical management, but could be a candidate for sentinel lymph node sampling alone if converted to node-negative disease with neoadjuvant therapy
Surgery must be postponed awaiting consultation with plastic surgery regarding breast reconstruction, results of genetic testing, or resolution of an intercurrent illness, including pregnancy, and the patient and treating clinicians do not wish to delay initiation of treatment
Postoperative treatment with ado-trastuzumab emtansine (T-DM1) would be considered if the patient were found to have residual invasive disease in the breast or axillary nodes following NAC with single or dual HER2-targeted therapy
Pertuzumab:
Is a monoclonal antibody that binds to a different epitope on HER2 than trastuzumab:
Blocking the formation of HER2:HER3 heterodimers:
Which is believed to be an important mechanism of resistance to trastuzumab
While single-agent pertuzumab has demonstrated antitumor activity in patients with HER2-positive metastatic disease who progressed on trastuzumab:
It is typically given in combination with trastuzumab to maintain suppression of signaling initiated by HER2 homodimers
In 2013, the FDA granted accelerated approval for the addition of pertuzumab to NACT and trastuzumab:
For patients with HER2+ locally advanced, inflammatory, or early-stage (either greater than 2 cm in diameter or node positive) breast cancer
We routinely add pertuzumab in patients receiving NACT and trastuzumab:
Given evidence that pertuzumab enhances locoregional responses:
Even though it increases the incidence and severity of treatment-related diarrhea as well as modestly increasing the frequency of hematologic toxicities
NeoSphere trial:
In the phase II NeoSphere trial:
417 HER2+ patients received 12 weeks of neoadjuvant therapy composed of either 4 cycles of single-agent docetaxel with trastuzumab, pertuzumab, or both, or the combination of trastuzumab and pertuzumab without concurrent docetaxel
After surgery, all patients received anthracycline-based adjuvant chemotherapy (those randomized to trastuzumab and pertuzumab alone also received adjuvant docetaxel) and completed a year of treatment with trastuzumab
Those randomly assigned to docetaxel with pertuzumab and trastuzumab had a higher pathologic complete response (pCR) rate (46%):
Compared with those receiving docetaxel with just trastuzumab (29%) or just pertuzumab (24%)
Patients receiving pertuzumab and trastuzumab without docetaxel:
Had a pCR rate of 17%
References
Hayes DF. HER2 and breast cancer — a phenomenal success story. N Engl J Med. 2019;381(13):1284-1286.
Gianni L, Pienkowski T, Im Y-H, Tseng LM, Liu MC, Lluch A, et al. 5-Year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791-800.
It is recommended as one of the first lines of therapy for metastatic triple negative breast cancer:
Safety data are reported for its use in the elderly
In addition, because it is administered weekly:
It is easy to reduce the dose in the presence of toxicities
Local therapy:
Is not indicated for most patients with distant metastatic disease in the absence of symptoms
HER2 therapies:
Are not indicated in the treatment of HER2 negative tumors
Dose-dense doxorubicin and cyclophosphamide:
Is often part of the regimen for early-stage triple negative breast cancer:
Not metastatic disease
References
Li X, Kwon H. Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Elderly Patients with Metastatic Breast Cancer: A Meta-Analysis. J Clin Med. 2019 Oct 15;8(10).
Biganzoli L, Wildiers H, Oakman C, Marotti L, Loibl S, Kunkler I, et al. Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol. 2012;13(4):e148-e160.
Showed that the combination of docetaxel, trastuzumab, and pertuzumab:
Led to improved progression free survival (PFS) compared to docetaxel, trastuzumab, and placebo:
18.5 months vs. 12.4 months
Surgery for the primary site:
Is not indicated for patients with distant metastatic disease in the absence of symptoms
References
Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. New Engl J Med.2012;366(2):109-119.
Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734.
In women with ER+ breast cancer with up to 3 lymph nodes positive
It also predicts who is more likely to benefit from adjuvant chemotherapy
References
Dowsett M, Cuzick J, Wale C, Forbes J, Mallon EA, Salter J, et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol. 2010;29(11):1829-1834.
Roberts MC, Miller DP, Shak S, Petkov VI. Breast cancer-specific survival in patients with lymph node-positive hormone receptor-positive invasive breast cancer and Oncotype DX Recurrence Score results in the SEER database. Breast Cancer Res Treat.2017;163(2):303-310.
Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer:
Now with a median follow-up of 10.4 years:
Confirmed the benefit of adding pertuzumab to trastuzumab plus chemotherapy:
In preventing invasive disease recurrences, but as yet no statistically significant overall survival benefit has emerged
The long-term outcomes of both arms remain very good:
With more than 92% of patients alive at 8 years:
The overall survival analysis remains immature:
But the difference of 0.7% numerically favors the pertuzumab arm
Key Findings of Aphinity trial:
In the thirdinterim analysis, fewer deaths were seen in the pertuzumab arm compared with the placebo arm:
By January 10, 2022, deaths totaled 168 in the pertuzumab arm (7.0%) and 202 in the placebo arm (8.4%)
The 8-year overall survival percentages were 92.7% vs 92.0%, respectively – a 0.7% difference (hazard ratio [HR] = 0.83; P = .078; 95% confidence interval [CI] = 0.68–1.02)
For invasive disease–free survival, the primary endpoint:
The updated descriptive analysis revealed a 2.6% absolute benefit for pertuzumab (HR = 0.77; 95% CI = 0.66–0.91):
Consistent with the 2.8% increase from the 6-year analysis, she further reported
Of note, the sustained benefit with pertuzumab was driven by its impact on the node-positive cohort:
The absolute benefit of dual HER2 blockade in this cohort was 1.9% for overall survival and 4.9% for invasive disease–free survival
In contrast, patients with node-negative disease derived no additional benefit:
From the second anti-HER2 agent
Interestingly, although not shown in previous analyses:
The addition of pertuzumab conferred an advantage in both hormone receptor negative and positive patients
Two key takeaways from the latest findings:
The node-positive cohort derives benefit from adding pertuzumab
And with longer follow-up beyond the first 3 years, the data clearly show that hormone receptor status should not guide pertuzumab treatment decisions
REFERENCES
Loibl S, Jassem J, Sonnenblick A, et al: Updated results of APHINITY at 8.4 years median follow-up. ESMO Virtual Plenary. Abstract VP6-2022l. Presented July 14, 2022.
Piccart M, Procter M, Fumagalli D, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY Trial: 6 years’ follow-up. J Clin Oncol 39:1448-1457, 2021.
Von Minckwitz G, Procter M, de Azambuja E, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 377:122-131, 2017.
Including those who achieve pathologic complete response after neoadjuvant chemotherapy
One could also consider continuing adjuvant pertuzumab in addition to trastuzumab:
Based on results from the phase III Aphinity trial:
Although patients who received neoadjuvant chemotherapy were not included in this trial
For patients who have residual disease and do not achieve complete pathologic response at the time of surgery:
Completion of 1 year of trastuzumab emtansine (T-DM1):
Decreased the risk of recurrence of invasive breast cancer or death by 50% than with trastuzumab alone:
Based on results from KATHERINE trial:
The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group
References
von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. Adjuvant Pertuzumab and Trastuzumab in early HER2-positive breast cancer N Engl J Med. 2017;377(2):122-131.
von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.
👉 TAX 324 Posner, M.D et al Cisplatin and Fluorouracil Alone or with Docetaxel in Head and Neck Cancer.
👉Background
A randomized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck:
Compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF), followed by chemoradiotherapy
👉 Methods
In the TAX 324 they randomly assigned 501 patients:
All of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation:
To receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy:
With weekly carboplatin therapy and radiotherapy for 5 days per week
The primary end point was overall survival
👉 Results
With a minimum of two-years of follow-up (≥ 3 years for 69% of patients):
Significantly more patients survived in the TPF group than in the PF group:
Hazard ratio for death, 0.70; P=0.006
Estimates of overall survival at three-years were:
62% in the TPF group
48% in the PF group
The median overall survival was:
71 months in the TPF
30 months in the PF:
P = 0.006
There was better locoregional control in the TPF group than in the PF group (P=0.04)
The incidence of distant metastases in the two groups did not differ significantly (P=0.14)
Rates of neutropenia and febrile neutropenia were higher in the TPF group
Chemotherapy was more frequently delayed because of hematologic adverse events in the PF group
👉 Conclusions
Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy:
Had a significantly longer survival than did patients who cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy:
Prospective randomized trials addressing the safety of breast reconstruction in the older patient population don’t exist, and are unlikely to take place in the future
The available literature largely consists of single institution experiences with various types of breast reconstruction in older patients
This data shows that, in the older breast cancer patients determined to be good candidates for breast reconstruction:
The latter is generally safe in this patient population
A study by Sada et al from the Mayo Clinic reported that, among women 65 years and older who underwent immediate breast reconstruction:
12.6% experienced postoperative complications
Whereas women younger than 65 had a lower complication rate of 6.8% (p=0.04)
Similarly, older patients undergoing immediate breast reconstruction:
Were more likely to require a reoperation for postoperative hematoma:
5.3% vs. 0.9%, p=0.006
It is reassuring that complication rates are quite low overall, and there were no differences between older and younger patients undergoing breast reconstruction with respect to skin flap necrosis or unplanned readmission
Autologous breast reconstruction performed in carefully selected patients 65 years and older has also been reported to be safe and successful, as has been shown in a single institution report by Brendler-Spaeth et al, and in another retrospective series by Wähmann et al
Additionally, Brendler-Spaeth et al reported that immediate and delayed autologous breast reconstruction in older breast cancer patients was associated with similarly low complication rates
Furthermore, autologous breast reconstruction was shown to be associated with better long-term aesthetic outcomes in older breast cancer patients based on the meta-analysis by Hamnett and Subramanian
Rates of breast reconstruction in elderly patients are lower than among younger patients:
Approximately 1% versus 45%, respectively
A single institution study by Siotos et al demonstrated that older age was an independent risk factor for not receiving breast reconstruction (OR=0.18, 95%CI:0.08-0.40)
The existing literature is limited in that it is not possible to discern whether older patients are not being offered breast reconstruction as often as their younger counterparts or if they are less likely to opt for it
The available data demonstrate rather low complication rates reported in older breast cancer patients undergoing breast reconstruction, and they underscore an opportunity to extend the option of breast reconstruction to older patients interested in pursuing it and deemed to be good surgical candidates
References
Dolen UC, Law J, Tenenbaum MM, Myckatyn TM. Breast reconstruction is a viable option for older patients. Breast Cancer Res Treat. 2022;191(1):77-86. doi: 10.1007/s10549-021-06389-z
Chang-Azancot L, Abizanda P, Gijón M, et al. Age and breast reconstruction. Aesth Plast Surg. 2023;47(1):63-72. doi: 10.1007/s00266-022-03024-0
Sada A, Day CN, Hoskin TL, Degnim AC, Habermann EB, Hieken TJ. Mastectomy and immediate breast reconstruction in the elderly: trends and outcomes. Surgery. 2019;166(4):709-714. doi: 10.1016/j.surg.2019.05.055
Brendler-Spaeth CI, Jacklin C, See JL, Roseman G, Kalu PU. Autologous breast reconstruction in older women: a retrospective single-centre analysis of complications and uptake of secondary reconstructive procedures. J Plast Reconstr Aesthet Surg. 2020;73(5):856-864. doi: 10.1016/j.bjps.2019.11.039
Wähmann M, Wähmann M, Henn D, et al. Geriatric patients with free flap reconstruction: a comparative clinical analysis of 256 cases. J Reconstr Microsurg. 2020;36(2):127-135. doi: 10.1055/s-0039-1697646
Hamnett KE, Subramanian A. Breast reconstruction in older patients: a literature review of the decision-making process. J Plast Reconstr Aesthet Surg. 2016;69(10):1325-1334. doi: 10.1016/j.bjps.2016.06.003
Lee RXN, Cardoso MJ, Cheung KL, Parks RM. Immediate breast reconstruction uptake in older women with primary breast cancer: a systematic review. Br J Surg. 2022; 109(11):1063-1072. doi: 10.1093/bjs/znac251
Siotos C, Lagiou P, Cheah MA, et al. Determinants of receiving immediate breast reconstruction: an analysis of patient characteristics at a tertiary care center in the US. Surg Oncol. 2020;34:1-6. doi: 10.1016/j.suronc.2020.02.017
The management of breast cancer has become increasingly complex and multidisciplinary, with increasing imaging studies, appointments, and often, second or third opinions patients seek for care
Together, many of these factors have led to lengthening time intervals between diagnosis and surgery
At the same time, time from diagnosis to surgical treatment of 60 days:
Is now a Commission on Cancer quality metric
Minimizing delays in treatment is a sensical goal believed to lead to improved outcomes
The precise time frame that is considered reasonable and safe versus detrimental to breast cancer survival is not known, although a number of recent large retrospective studies have evaluated this.
Bleicher et al:
In a 2016 study of nearly 100,000 women > 65 years of age in the SEER-Medicare database
Showed that overall survival decreased by 9% after a 60-day delay from diagnosis to surgery
In addition, the association between overall survival and time to surgery:
Was significant for stage I (HR 1.13, p<0.001) and stage II (HR 1.06, p<0.01):
But not for stage III breast cancer patients
The association between breast cancer-specific survival and time to surgery (HR 1.84, p=0.02) persisted solely for stage I patients:
Likely attributable to the baseline mortality in this group being smaller than the relative impact imposed by a delay in treatment
A 2020 study of ~ 350,000 patients (of all ages) in the NCDB with stage I to III breast cancer treated with up front surgical therapy examined the relationship between overall survival, time to surgery, and biologic subtype of breast cancer (i.e. triple negative, ER+PR+, HER2+):
Prevailing opinion prior to this study was that delays would be more detrimental to those with more biologically aggressive tumors such as TN or HER2+ due to downstream delays in adjuvant systemic therapy resulting from delayed surgical treatment
This study found that overall survival was observed to decline with every month delay in surgical treatment (HR 1.1, p<0.001):
This did not vary by biologic subtype (p>0.33).
A more recent 2023 study of NCDB stage I to III breast cancer patients treated with up front surgery analyzed survival for every one-week interval after 30 days post-diagnosis
Median time to surgery was 30 days:
90% of patients underwent surgery within 60 days
Delays of 9 weeks or greater were found to be more common in younger women and the uninsured
They found that there was no significant association between time to surgery and survival for any of the groups:
Until after 9 weeks post-diagnosis
A surgical delay of 9 weeks or longer after diagnosis was associated with worse overall survival (HR 1.15, p < 0.001):
Compared with surgery within 4 weeks of diagnosis
Again, no significant interaction was found between tumor biologic subtype and time to surgery’s association with survival
Therefore, the conclusion was made that 8 weeks or shorter serve as a standard quality metric for timeliness of surgery.
References
Bleicher RJ et al. Preoperative delays in the US Medicare population with breast cancer. J Clin Oncol 2012; 30:4485-92
Bleicher RJ et al. Time to Surgery and Breast Cancer Survival in the United States. JAMA Surg 2016; 2:330-9
Mateo AM et al. Time to Surgery and the Impact of Delay in the Non-Neoadjuvant Setting on Triple-Negative Breast Cancers and Other Phenotypes. Ann Surg Oncol 2020; 27:1679-92
Wiener AA et al. Reexamining Time From Breast Cancer Diagnosis to Primary Breast Surgery. JAMA Surg 2023; 158:485-92
